Kinesin Family Member Research Articles

Genome-Wide Identification of the Kinesin Gene Family in Soybean and Its Response to Salt Stress

The kinesin (KIN) gene family is a subgroup of motor proteins. It plays a critical role in plant development and responses to environmental stresses. However, their function in soybean salt tolerance has yet to be clearly defined. This study employed bioinformatics approaches and identified 139 kinesin family members in the soybean genome. These 139 genes were classified into 10 subgroups, unevenly distributed across the chromosomes. The promoter regions of GmKIN genes harbored several stress-responsive elements, and segmental duplication was the primary driver of the expansion of the GmKIN gene family. Based on publicly available RNA-seq data, we studied the response patterns of 139 GmKIN genes to salt stress and found that 20 KIN genes in soybeans were upregulated after salt stress, with GmKIN114, GmKIN102, GmKIN109, and GmKIN99 showing more than a threefold increase in their expression under salt stress. Using quantitative fluorescence PCR, transgenic yeast, and a transgenic hairy root system, we preliminarily validated the salt tolerance functions of the four KIN genes in soybeans. This study probed into the GmKIN gene family in soybean, offering valuable insights into the functional roles of these genes in stress adaptation.

KIF9 Ameliorates Neuropathology and Cognitive Dysfunction by Promoting Macroautophagy in a Mouse Model of Alzheimer's Disease.

Alzheimer's disease (AD) is a prevalent neurodegenerative disorder affecting the elderly. The imbalance of protein production and degradation processes leads to the accumulation of misfolded and abnormally aggregated amyloid-beta (Aβ) in the extracellular space and forms senile plaques, which constitute one of the most critical pathological hallmarks of AD. KIF9, a member of the kinesin protein superfamily, mediates the anterograde transport of intracellular cargo along microtubules. However, the exact role of KIF9 in AD pathogenesis remains largely elusive. In this study, we reported that the expression of kinesin family member 9 (KIF9) in the hippocampus of APP23/PS45 double-transgenic AD model mice declined in an age-dependent manner, concurrent with macroautophagy dysfunction. Furthermore, we found that KIF9 mediated the transport of lysosomes through kinesin light chain 1 (KLC1), thereby participating in the degradation of amyloidogenic pathway-related proteins of Aβ precursor protein (APP) in AD model cells through promoting the macroautophagy pathway. Importantly, genetic upregulation of KIF9 via adeno-associated virus (AAV) diminished Aβ deposition and alleviated cognitive impairments in AD model mice by enhancing macroautophagy function. Collectively, our findings underscore the ability of KIF9 to promote macroautophagy through KLC1-mediated anterograde transport of lysosomes, effectively ameliorating cognitive dysfunction in AD model mice. These discoveries suggest that KIF9 may represent a novel therapeutic target for the treatment of AD.

High interstitial fluid pressure enhances USP1-dependent KIF11 protein stability to promote hepatocellular carcinoma progression

BackgroundHCC is characterized by a high interstitial fluid pressure (HIFP) environment, which appears to support cancer cell survival. However, the mechanisms behind this phenomenon are not fully understood.MethodsThis study investigates the role of kinesin family member 11 (KIF11) in HCC under HIFP conditions, using both in vivo and in vitro models. In vitro experiments replicated the HIFP environment to observe changes in HCC cell behavior and protein expression, while in vivo studies involved mice portal hypertension to create an orthotopic liver cancer model, allowing for the evaluation of tumor progression. Additionally, clinical samples from HCC patients were analyzed for consistency with the experimental findings.ResultsResults demonstrated that the HIFP environment significantly increased the proliferation, invasion, and metastasis in HCC cells. Omics analysis and subsequent molecular validation revealed that KIF11 protein levels were markedly upregulated under HIFP, despite no significant change in mRNA levels. Further investigation showed that this upregulation was linked to a reduction in KIF11's ubiquitin-mediated degradation, suggesting that the HIFP environment stabilizes KIF11 expression by inhibiting its degradation pathway. Co-immunoprecipitation and proteomic analysis identified ubiquitin-specific peptidase 1 (USP1) as a crucial factor in this process, deubiquitinating KIF11 at the K77 site, thus stabilizing its protein levels. Clinical analysis confirmed that both USP1 and KIF11 were significantly overexpressed in HCC patients with portal hypertension, with a strong correlation between the two. Inhibition of USP1 using ML323 significantly reduced KIF11 protein levels and suppressed tumor progression in the mouse model.ConclusionThese findings suggest that the HIFP environment fosters HCC progression through USP1-mediated stabilization of KIF11, highlighting USP1 as a potential therapeutic target, especially in patients with portal hypertension.

Identification and validation of the important role of KIF11 in the development and progression of endometrial cancer

Identification and validation of the important role of KIF11 in the development and progression of endometrial cancer

Molecular Mechanisms of circKIF4A in Breast Cancer Progression.

Breast cancer (BC) is the most frequently diagnosed malignancy worldwide, necessitating continued research into its molecular mechanisms. Circular RNAs (circRNAs) are increasingly recognized for their role in various cancers, including BC. This study explores the role of circRNA kinesin family member 4A (circKIF4A) in BC progression and its underlying molecular mechanisms. BC cell lines were cultured, and circKIF4A expression was knocked down. Cell viability, proliferation, migration, and invasion were assessed using the Cell Counting Kit-8, colony formation assay, and Transwell assays. The expression of circKIF4A, miR-874-3p, and glycerophosphodiester phosphodiesterase domain-containing 5 (GDPD5) was quantified using qRT-PCR and Western blot analysis. Subcellular fractionation was performed to localize circKIF4A within the cell. The interactions between circKIF4A and miR-874-3p, as well as between miR-874-3p and GDPD5, were evaluated using RNA pull-down and dual-luciferase assays. Rescue experiments were conducted with miR-874-3p inhibition or GDPD5 overexpression to confirm the mechanistic pathway. circKIF4A was found to be upregulated in BC cells. Its knockdown significantly inhibited cell proliferation, migration, and invasion. circKIF4A acts as a sponge for miR-874-3p, reducing its expression. miR-874-3p targets and suppresses GDPD5, a key regulator in BC cell growth. Silencing miR-874-3p or overexpressing GDPD5 reversed the tumor-suppressive effects of circKIF4A knockdown. circKIF4A promotes BC cell proliferation and invasiveness by regulating the miR-874-3p/GDPD5 axis. These findings highlight a potential therapeutic target in BC and contribute to the understanding of circRNA involvement in cancer progression.

Insufficient MIRO1 contributes to declined oocyte quality during reproductive aging.

Mitochondrial Rho-GTPase 1 (MIRO1) is an outer mitochondrial membrane protein which regulates mitochondrial transport and mitophagy in mitosis. In present study, we reported the crucial roles of MIRO1 in mammalian oocyte meiosis and its potential relationship with aging. We found that MIRO1 expressed in mouse and porcine oocytes, and its expression decreased in aged mice. MIRO1 deficiency caused the failure of meiotic resumption and polar body extrusion in both mouse and porcine oocytes, which could be rescued by exogenous MIRO1 supplementation. Mass spectrometry data indicated that MIRO1 associated with several cytoskeleton and cell cycle-related proteins, and MIRO1 regulated motor protein Dynein for microtubule-organizing centers (MTOCs) dynamics at germinal vesicle (GV) stage, which determined meiotic resumption. Furthermore, we found that MIRO1 regulated Aurora A and kinesin family member 11 (KIF11) for meiotic spindle assembly in oocytes. Besides, MIRO1 associated with several mitochondria-related proteins dynamic-related protein 1 (DRP1), Parkin and lysosomal-associated membrane protein 2 (LAMP2) for mitochondrial dynamics and mitophagy during oocyte meiosis. Taken together, our results suggested that MIRO1 played pivotal roles in meiotic resumption, spindle assembly and mitochondrial function in mouse and porcine oocytes, and its insufficiency might contribute to the oocyte maturation defects during aging.

CBX3 contributes to pancreatic adenocarcinoma progression via promoting KIF20A expression.

Pancreatic adenocarcinoma (PAAD) is one of the malignant tumors with poor prognosis. This study aims to inquiry the effects of Chromobox homologue 3 (CBX3) on PAAD progression. Pan-cancer analysis of CBX3 and its correlation with PAAD progression were investigated by informatics analysis. The role of CBX3 in PAAD was explored in vitro and in vivo. Cell viability, proliferation, migration and invasion were inspected by CCK-8 assay, EdU staining, scratch test and transwell assay, respectively. The morphology of tumors was observed by hematoxylin-eosin staining. Immunohistochemistry (Ki67) was performed to inspect the proliferation of tumor tissue. The protein levels were measured by western blot. Moreover, the downstream genes of CBX3 were screened, and the effects of target gene on PAAD was investigated in vitro. CBX3 was overexpressed in multi cancers, and high CBX3 expression indicated poor prognosis in PAAD. Through the in vitro assays, knockdown of CBX3 suppressed the viability, migration and invasion of PAAD cells, and restrained tumor growth in vivo. Subsequently, kinesin family member 20A (KIF20A) was screened as the downstream gene of CBX3, which was up-regulated in PAAD and related to low overall survival. Mechanistically, we discovered that CBX3 could regulate KIF20A expression. Knockdown of CBX3 promoted the oncogenic effects of KIF20A silencing on PAAD cells, and attenuated the pro-oncogenic effects of KIF20A overexpression on PPAD. Collectively, silencing CBX3 suppressed PAAD progression through regulating KIF20A expression, providing an underlying target for PAAD treatment.

TFDP1 transcriptionally activates KIF22 to enhance aggressiveness and stemness in endometrial cancer: implications for prognosis and targeted therapy.

This study aims to elucidate the role of Kinesin Family Member 22 (KIF22) as a critical regulator of aggressive behavior in endometrial cancer (uterine corpus endometrial carcinoma, UCEC) and to uncover its underlying mechanisms, thereby providing a molecular rationale for future targeted treatment. Bioinformatics analyses were employed to assess KIF22 and TFDP1 expression in UCEC, examining their prognostic value and associations with disease progression. Expression levels were validated in UCEC tissues using qRT-PCR and western blotting. Potential TFDP1 binding sites on the KIF22 promoter were predicted using the JASPAR database and confirmed via dual-luciferase reporter assays. Functional assays, including CCK-8, transwell, and spheroid formation assays, were conducted to evaluate the effects of KIF22 knockdown on UCEC cell behavior. A mouse xenograft model was utilized to investigate the in vivo impact of KIF22 suppression on tumor growth and stemness. KIF22 expression was significantly elevated in UCEC tissues, correlating with reduced overall survival in patients with high KIF22 levels. Overexpression of KIF22 enhanced the proliferation, migration, and sphere formation of UCEC cells. Similarly, high TFDP1 expression was associated with poorer patient outcomes. KIF22 was found to be positively regulated by the TFDP1 transcription factor, which bound to the KIF22 promoter and activated its expression in UCEC cells. In vivo, KIF22 knockdown markedly impeded the tumor formation of cells and reduced stemness marker expression. KIF22, upregulated by TFDP1, enhances UCEC cell aggressiveness and is linked to poor prognosis, highlighting its potential as a target for therapeutic intervention in endometrial cancer.

Injury-induced KIF4A neural expression and its role in Schwann cell proliferation suggest a dual function for this kinesin in neural regeneration.

Contrary to the adult central nervous system, the peripheral nervous system has an intrinsic ability to regenerate that relies on the expression of regeneration-associated genes, such as some kinesin family members. Kinesins contribute to nerve regeneration through the transport of specific cargo, such as proteins and membrane components, from the cell body towards the axon periphery. We show here that KIF4A, associated with neurodevelopmental disorders and previously believed to be only expressed during development, is also expressed in the adult vertebrate nervous system and up-regulated in injured peripheral nervous system cells. KIF4A is detected both in the cell bodies and regrowing axons of injured neurons, consistent with its function as an axonal transporter of cargoes such as β1-integrin and L1CAM. Our study further demonstrates that KIF4A levels are greatly increased in Schwann cells from injured distal nerve stumps, particularly at a time when they are reprogrammed into an essential proliferative repair phenotype. Moreover, Kif4a mRNA levels were approximately ~6-fold higher in proliferative cultured Schwann cells compared with non-proliferative ones. A hypothesized function for Kif4a in Schwann cell proliferation was further confirmed by Kif4a knockdown, as this significantly reduced Schwann cell proliferation in vitro. Our findings show that KIF4A is expressed in adult vertebrate nervous systems and is up-regulated following peripheral injury. The timing of KIF4A up-regulation, its location during regeneration, and its proliferative role, all suggest a dual role for this protein in neuroregeneration that is worth exploring in the future.

Anapc5 and Anapc7 as genetic modifiers of KIF18A function in fertility and mitotic progression.

The kinesin family member 18A (KIF18A) is an essential regulator of microtubule dynamics and chromosome alignment during mitosis. Functional dependency on KIF18A varies by cell type and genetic context but the heritable factors that influence this dependency remain unknown. To address this, we took advantage of the variable penetrance observed in different mouse strain backgrounds to screen for loci that modulate germ cell depletion in the absence of KIF18A. We found a significant association at a Chr5 locus where anaphase promoting complex subunits 5 (Anapc5) and 7 (Anapc7) were the top candidate genes. We found that both genes were differentially expressed in a sensitive strain background when compared to resistant strain background at key timepoints in gonadal development. We also identified a novel retroviral insertion in Anapc7 that may in part explain the observed expression differences. In cell line models, we found that depletion of KIF18A induced mitotic arrest, which was partially rescued by co-depletion of ANAPC7 (APC7) and exacerbated by co-depletion of ANAPC5 (APC5). These findings suggest that differential expression and activity of Anapc5 and Anapc7 may influence sensitivity to KIF18A depletion in germ cells and CIN cells, with potential implications for optimizing antineoplastic therapies.

Role of KIF20A Depletion in Inhibiting Ovarian Cancer Progression: Insights From PTEN and M2 Macrophage Polarization.

Recent studies have proven the oncogenic role of kinesin family member 20A (KIF20A) in several cancers. Tumor-associated macrophages (TAMs) were reported to participate in tumor initiation and metastasis. In this study, we aimed to explore the detailed mechanism underlying KIF20A in regulating the progression of ovarian cancer and its involvement with TAMs. KIF20A and phosphatase and tensin homolog (PTEN) levels were assessed using reverse-transcription quantitative polymerase chain reaction (RT-qPCR) and western blot. Cell Counting Kit-8 (CCK-8) assay, 5-Ethynyl-2'-deoxyuridine (EdU) staining assay, colony formation assay, flow cytometry, and western blot were employed to evaluate cell proliferation, apoptosis, and epithelial-mesenchymal transition (EMT). The relationship between KIF20A and PTEN was validated using a dual-luciferase assay. M2 macrophage polarization was verified by detecting their markers using RT-qPCR. THP-1 cells were co-cultured with ovarian cancer cells to format TAMs. Ovarian cancer tissues and cells exhibited upregulated KIF20A and downregulated PTEN levels (p < 0.05). Irradiation significantly decreased KIF20A levels (p < 0.05) and blunted the progression of ovarian cancer by reducing cell proliferation and EMT (p < 0.05) and inducing apoptosis (p < 0.05). These effects were augmented by KIF20A depletion (p < 0.05). KIF20A depletion also suppressed ovarian cancer cell progression (p < 0.05). Our findings illustrated that KIF20A negatively regulated PTEN expression in ovarian cancer cells. Moreover, the inhibitory effects of KIF20A depletion on ovarian cancer development in irradiated ovarian cancer cells were obviously impeded by PTEN knockdown (p < 0.05). Additionally, we observed the increased KIF20A expression in M2-like TAMs and its ability to induce M2 macrophage polarization (p < 0.05). KIF20A was found to induce M2 macrophage polarization in ovarian cancer, and KIF20A depletion regulated PTEN to increase radiosensitivity and inhibit ovarian cancer development.

KIF18A and CDK1 as combined therapeutic targets in cervical and endometrial carcinomas: based on bioinformatics analysis and in vitro experiments.

Chromosomal instability (CIN) has been identified as a factor that increases the susceptibility of tumor cells to kinesin family member 18A (KIF18A) inhibitors. Limited research exists on genes that are associated with sensitization to KIF18A inhibitors (KIF18Ais). Our study aimed to identify a gene linked to heightened sensitivity to KIF18Ais in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) and uterine corpus endometrial carcinoma (UCEC). The Cancer Genome Atlas (TCGA) and X2K Appyter databases were used to analyze potential kinases associated with KIF18A-related genes in CESC and UCEC. In vitro assessments, such as Cell Counting Kit-8 (CCK-8), transwell, and terminal-deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) assays, were performed to evaluate the combined effects of KIF18A and cyclin-dependent kinase 1 inhibitors (CDK1is) in CESC and UCEC cell lines. Our findings indicated that the combination of KIF18A with kinases may potentially augment the efficacy of KIF18Ais, given its close involvement in cell cycle and chromosome segregation. Through bioinformatics analysis, we observed a significant up-regulation of CDK1 expression in CESC and UCEC, which exhibited a strong correlation with KIF18A expression. Our hypothesis regarding the potential of CDK1 as a combination therapeutic target for KIF18A was supported by our cell experiments, which demonstrated that inhibition of CDK1 notably increased the sensitivity of CESC and UCEC cells to KIF18Ais. The combined use of CDK1is and KIF18Ais exhibited a synergistic effect in inhibiting cell migration and inducing apoptosis in CESC and UCEC cells. This study provides evidence that targeting both KIF18A and CDK1 exerts synergistic anti-tumor effects in CESC and UCEC via inhibiting cell proliferation and migration and inducing apoptosis, suggesting a promising therapeutic strategy for these cancers.

Identification of Crucial Cancer Stem Cell Genes Linked to Immune Cell Infiltration and Survival in Hepatocellular Carcinoma.

Hepatocellular carcinoma is characterized by high recurrence rates and poor prognosis. Cancer stem cells contribute to tumor heterogeneity, treatment resistance, and recurrence. This study aims to identify key genes associated with stemness and immune cell infiltration in HCC. We analyzed RNA sequencing data from The Cancer Genome Atlas to calculate mRNA expression-based stemness index in HCC. A weighted gene co-expression network analysis was performed to identify stemness-related gene modules. A single-sample gene set enrichment analysis was used to evaluate immune cell infiltration. Key genes were validated using RT-qPCR. The mRNAsi was significantly higher in HCC tissues compared to adjacent normal tissues and correlated with poor overall survival. WGCNA and subsequent analyses identified 10 key genes, including minichromosome maintenance complex component 2, cell division cycle 6, forkhead box M1, NIMA-related kinase 2, Holliday junction recognition protein, DNA topoisomerase II alpha, denticleless E3 ubiquitin protein ligase homolog, maternal embryonic leucine zipper kinase, protein regulator of cytokinesis 1, and kinesin family member C1, associated with stemness and low immune cell infiltration. These genes were significantly upregulated in HCC tissues. A functional enrichment analysis revealed their involvement in cell cycle regulation. This study identified 10 key genes related to stemness and immune cell infiltration in HCC. These genes, primarily involved in cell cycle regulation, may serve as potential targets for developing more effective treatments to reduce HCC recurrence and improve patient outcomes.

Ergotamine Targets KIF5A to Facilitate Anoikis in Lung Adenocarcinoma.

Kinesin family member 5A (KIF5A) has been reported to be closely related to cancer progression. The aim of this study was to investigate the effect of KIF5A on lung adenocarcinoma (LUAD) and its potential molecular mechanisms. Using bioinformatics analysis methods and molecular experiments, the expression of KIF5A in LUAD was analyzed, with its expression in attached and detached tumor cells assessed. Gene set enrichment analysis (GSEA) of KIF5A was carried out. The small molecular drug with the highest affinity for KIF5A was screened out through molecular docking experiments, which was validated through cellular thermal shift assay (CETSA). Quantitative polymerase chain reaction (qPCR) was employed to measure the expression levels of anoikis-repressing genes (BCL2, CAV1), as well as anoikis-inducing gene (PDCD4). CCK-8 assay was applied to examine cell viability. Cell colony formation experiments were utilized to evaluate cell proliferation ability. We observed that KIF5A was highly upregulated in LUAD tissues and cells, with a higher level detected in detached LUAD cells. By resorting to bioinformatics analysis, we discovered that KIF5A was abundant in the anoikis pathway. Knocking down KIF5A reinforced anoikis in LUAD. Further screening identified Ergotamine as the small molecular drug with the highest affinity for KIF5A. The CETSA confirmed the binding relationship between the two. In addition, Ergotamine has a promoting effect on the anoikis of LUAD, while overexpression of KIF5A reversed the effects of Ergotamine on LUAD cells. This project uncovered that the small molecular drug Ergotamine targets and inhibits the expression of KIF5A. Downregulated KIF5A can enhance the anoikis of LUAD. Our results supported the inhibition of KIF5A as an attractive therapeutic strategy for LUAD. This finding provides a new innovative pathway for the treatment of LUAD and offers a strong theoretical basis for the development of therapeutic drugs targeting KIF5A.

Unraveling the interplay of kinesin-1, tau, and microtubules in neurodegeneration associated with Alzheimer's disease.

Alzheimer's disease (AD) is marked by the gradual and age-related deterioration of nerve cells in the central nervous system. The histopathological features observed in the brain affected by AD are the aberrant buildup of extracellular and intracellular amyloid-β and the formation of neurofibrillary tangles consisting of hyperphosphorylated tau protein. Axonal transport is a fundamental process for cargo movement along axons and relies on molecular motors like kinesins and dyneins. Kinesin's responsibility for transporting crucial cargo within neurons implicates its dysfunction in the impaired axonal transport observed in AD. Impaired axonal transport and dysfunction of molecular motor proteins, along with dysregulated signaling pathways, contribute significantly to synaptic impairment and cognitive decline in AD. Dysregulation in tau, a microtubule-associated protein, emerges as a central player, destabilizing microtubules and disrupting the transport of kinesin-1. Kinesin-1 superfamily members, including kinesin family members 5A, 5B, and 5C, and the kinesin light chain, are intricately linked to AD pathology. However, inconsistencies in the abundance of kinesin family members in AD patients underline the necessity for further exploration into the mechanistic impact of these motor proteins on neurodegeneration and axonal transport disruptions across a spectrum of neurological conditions. This review underscores the significance of kinesin-1's anterograde transport in AD. It emphasizes the need for investigations into the underlying mechanisms of the impact of motor protein across various neurological conditions. Despite current limitations in scientific literature, our study advocates for targeting kinesin and autophagy dysfunctions as promising avenues for novel therapeutic interventions and diagnostics in AD.

VASH2 enhances KIF3C-mediated EGFR-endosomal recycling to promote aggression and chemoresistance of lung squamous cell carcinoma by increasing tubulin detyrosination

Lung squamous cell carcinoma (LUSC) is associated with high mortality and has few therapeutic options. Chemotherapy remains the main treatment for LUSC patients, but multi-drug resistance has become the dominant challenge in the failure of chemotherapy in various cancers. Therefore, the effective therapeutic strategy for LUSC patients is an urgent unmet need. Here, we found vasohibin-2 (VASH2) was a prognostic biomarker for LUSC patients, and VASH2 promoted the malignant biological behaviors of LUSC cells and chemoresistance by increasing the detyrosination of α-tubulin. The high level of detyrosinated-tubulin was negatively associated with patient prognosis. Blocking the tubulin carboxypeptidase (TCP) activity of VASH2 inhibited the xenograft tumor growth and improved the treatment efficacy of paclitaxel in vivo. Results revealed that VASH2-induced increase in tubulin detyrosination boosted the binding of kinesin family member 3C (KIF3C) to microtubules and enhanced KIF3C-dependent endosomal recycling of EGFR, leading to the prolonged activation of PI3K/Akt/mTOR signaling. This study demonstrated that VASH2 was not only a prognostic biomarker but also a promising therapeutic target in LUSC, which offers a novel insight that combination of chemotherapy and EpoY, a TCP inhibitor, may be a promising treatment strategy for LUSC patients.

KIF1C facilitates retrograde transport of lysosomes through Hook3 and dynein

Lysosomes, crucial cellular organelles, undergo bidirectional transport along microtubules, mediated by motor proteins such as cytoplasmic dynein-1 (dynein) and various kinesins. While the kinesin-3 family member KIF1C is established in mediating anterograde vesicle transport, its role in lysosomal transport remains unclear. Our study reveals that KIF1C unexpectedly supports the retrograde transport of lysosomes, driven by dynein, and contributes to their perinuclear localization. Notably, while KIF1C facilitates this perinuclear positioning, its motor activity is not required and, instead, exerts an inhibitory effect on this process. Mechanistically, KIF1C facilitates this process by interacting with the dynein-activating adaptor Hook3, which associates with the lysosome-anchored protein RUFY3. This regulatory mechanism is critical for the efficient degradation of cargo in autophagic and endocytic pathways. Our findings identify an unconventional, non-motor role for KIF1C in activating dynein-driven lysosomal transport, expanding our understanding of its functional diversity in cellular trafficking.

KIFC3 promotes the progression of non-small cell lung cancer cells through the PI3K/Akt pathway.

Kinesin family member C3 (KIFC3), as reported, plays important roles in several tumor types. Nevertheless, it is unknown whether KIFC3 has effects on non-small cell lung cancer (NSCLC) development. KIFC3 expression was detected by RT-PCR, and its correlation with prognosis was analyzed by GEPIA website. Small interfering RNA against KIFC3 were adopted for modulating KIFC3 expression in NSCLC cells. KIFC3 effects on NSCLC cell proliferation were determined using the MTT and clone formation assay. Matrigel invasion and wound healing assays were adopted for measuring the invasion and migration capability of NSCLC cells. Western blot was applied for measuring the levels of proteins associated with the phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt) pathway in NSCLC cells. KIFC3 was markedly increased in NSCLC samples and cells. KIFC3 knockdown suppressed the proliferation, invasion, and migration in NSCLC. Mechanically, KIFC3 silencing suppressed NSCLC progression through inhibiting the PI3K/Akt pathway. KIFC3 lack suppressed the proliferation, invasion, and migration which works, at least partially, by the PI3K/Akt pathway. These findings suggest that targeting KIFC3 via the PI3K/Akt pathway may offer a novel therapeutic strategy for NSCLC.

Tail-anchored membrane protein SLMAP3 is essential for targeting centrosomal proteins to the nuclear envelope in skeletal myogenesis.

The positioning and communication between the nucleus and centrosomes are essential in cell division, differentiation and tissue formation. During skeletal myogenesis, the nuclei become evenly spaced with the switch of the microtubule-organizing centre (MTOC) from the centrosome to the nuclear envelope (NE). We report that the tail-anchored sarcolemmal membrane associated protein 3 (SLMAP3), a component of the MTOC and NE, is crucial for myogenesis because its deletion in mice leads to a reduction in the NE-MTOC formation, mislocalization of the nuclei, dysregulation of the myogenic programme and abnormal embryonic myofibres. SLMAP3-/- myoblasts also displayed a similar disorganized distribution of nuclei with an aberrant NE-MTOC and defective myofibre formation and differentiation programming. We identified novel interactors of SLMAP3, including pericentrin, PCM1 (pericentriolar material 1), AKAP9 (A-kinase anchoring protein 9), kinesin-1 members Kif5B (kinesin family member 5B), KCL1 (kinesin light chain 1), KLC2 (kinesin light chain 2) and nuclear lamins, and observed that the distribution of centrosomal proteins at the NE together with Nesprin-1 was significantly altered by the loss of SLMAP3 in differentiating myoblasts. SLMAP3 is believed to negatively regulate Hippo signalling, but its loss was without impact on this pathway in developing muscle. These results reveal that SLMAP3 is essential for skeletal myogenesis through unique mechanisms involving the positioning of nuclei, NE-MTOC dynamics and gene programming.

KIFC1 depends on TRIM37-mediated ubiquitination of PLK4 to promote centrosome amplification in endometrial cancer

Endometrial cancer (EC), as one of the most common cancers, severely threatens female reproductive health. Our previous study has shown that Kinesin family member C1 (KIFC1) played crucial roles in the progression of EC. In addition, abnormal centrosome amplification, which was reported to be partially regulated by KIFC1, usually occurred in different cancers. However, whether KIFC1 promoted EC through centrosome amplification and the potential mechanism remain to be revealed. The present study demonstrated that overexpressed KIFC1, which exhibited a worse prognosis, had a positive correlation with an increased number of centrosomes in human EC samples. In addition, KIFC1 overexpression in EC cells prompted centrosome amplification, chromosomal instability, and cell cycle progression. Moreover, we demonstrated that KIFC1 inhibited E3 ubiquitin-protein ligase TRIM37 to maintain the stability of PLK4 by reducing its ubiquitination degradation, and finally promoting centrosome amplification and EC progression in vitro. Finally, the contributing role of KIFC1 and the inhibitory effect of TRIM37 on EC development and metastasis was verified in a nude mouse xenograft model. Our study elucidated that KIFC1 depends on TRIM37-mediated reduced ubiquitination degradation of PLK4 to promote centrosome amplification and EC progression, thus providing a potential prognostic marker and promising therapeutic target for EC in the future.