Abstract
The protein tyrosine phosphatase interacting protein 51 (PTPIP51) regulates and interconnects signaling pathways, such as the mitogen-activated protein kinase (MAPK) pathway and an abundance of different others, e.g., Akt signaling, NF-κB signaling, and the communication between different cell organelles. PTPIP51 acts as a scaffold protein for signaling proteins, e.g., Raf-1, epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (Her2), as well as for other scaffold proteins, e.g., 14-3-3 proteins. These interactions are governed by the phosphorylation of serine and tyrosine residues of PTPIP51. The phosphorylation status is finely tuned by receptor tyrosine kinases (EGFR, Her2), non-receptor tyrosine kinases (c-Src) and the phosphatase protein tyrosine phosphatase 1B (PTP1B). This review addresses various diseases which display at least one alteration in these enzymes regulating PTPIP51-interactions. The objective of this review is to summarize the knowledge of the MAPK-related interactome of PTPIP51 for several tumor entities and metabolic disorders.
Highlights
The mitogen-activated protein kinase (MAPK) pathway is one of the best described signaling system in cancer
30% of acute myeloid leukemia (AML) patients harbor some form of FMS-like tyrosine kinase 3 (FLT3) mutation, which can be divided itself into two mutational classes: internal tandem duplications (FLT3/ITD mutations) in or near the juxtamembrane domain of the receptor and point mutations resulting in single amino acid substitutions involving the activation loop of the tyrosine kinase domain (FLT3/TKD mutations) [94]
We highlight the central position of protein tyrosine phosphatase interacting protein 51 (PTPIP51) within the dysregulated MAPK pathway signaling of several disparate diseases
Summary
The mitogen-activated protein kinase (MAPK) pathway is one of the best described signaling system in cancer. The targets of ERK1/2 are diverse and include p90RSK, mitogen-activated protein kinase interacting protein kinases 1 and 2 (MNK1/2), Ets, Ets domain-containing protein (Elk1), Myc, signal transducer and activator of transcription 1/3 (STAT1/3) and estrogen receptor (ER), to name some of them [2] These many targets are necessary for the precise regulation of the various aforementioned cellular functions, e.g., differentiation, growth, apoptosis, and migration. High interaction levels of PTPIP51 and PTP1B as seen in normal and trained mice ensure the stimulating effect of PTPIP51 on MAPK pathway via dephosphorylation of the PTPIP51 Tyr176 residue and the formation of the Raf-1/14-3-3β/PTPIP51 complex [22]. A similar insulin sensitizing effect via transcriptional control of the insulin receptor as cited above for Drosophila could be possible [25] This hypothesis is supported by the upregulated interaction of 14-3-3β and PTPIP51 in high-fat diet, trained mice [22]. The functional and interactional consequences of PTP1B knockout or inhibition must be subject to further studies, as the aforementioned medical and economic implications strongly highlight the importance of the precise understanding of PTPIP51 in these signaling systems (Figure 1B)
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