Abstract
Emerging evidence implicates myristoylated alanine-rich C-kinase substrate (MARCKS), a major substrate of protein kinase C (PKC), in a critical role for cancer development and progression. MARCKS is tethered to the plasma membrane but can shuttle between the cytosol and plasma membrane via the myristoyl-electrostatic switch. Phosphorylation of MARCKS by PKC leads to its translocation from the plasma membrane to the cytosol where it functions in actin cytoskeletal remodeling, Ca2+ signaling through binding to calmodulin, and regulation of exocytic vesicle release in secretory cells such as neurons and airway goblet cells. Although the contribution of MARCKS to various cellular processes has been extensively studied, its roles in neoplastic disease have been conflicting. This review highlights the molecular and functional differences of MARCKS that exist between normal and tumor cells. We also discuss the recent advances in the potential roles of MARCKS in tumorigenesis, metastasis, and resistance to anti-cancer therapies, with a focus on addressing the inconsistent results regarding the function of MARCKS as a promoter or inhibitor of oncogenesis.
Highlights
The myristoylated alanine-rich C-kinase substrate (MARCKS) is a membrane-associated protein originally identified as a major target of protein kinase C (PKC) [1]
Studies of PKC in colorectal and breast cancer have shown that expression of different PKC isoforms vary among normal, primarytumor, and distant-metastasis tissue [71, 72], and we propose that upregulation of certain isoforms may lead to overphosphorylation of MARCKS in these and possibly other types of cancer
Observations connecting MARCKS to tumor malignancy are not novel, seemingly conflicting results and a dearth of detailed studies on the underlying mechanisms have made the exact role of MARCKS in neoplastic disease unclear
Summary
The myristoylated alanine-rich C-kinase substrate (MARCKS) is a membrane-associated protein originally identified as a major target of protein kinase C (PKC) [1]. Given that some of these processes are often dysregulated in neoplastic disease and co-opted by tumor cells to support their growth, proliferation, and invasion, it is reasonable to expect that MARCKS would play a role in tumorigenesis and metastasis. Due to intrinsic differences in the tissue origin and phenotype of the cancer cells, in certain malignancies, MARCKS appears to suppress the growth and invasion of cancer cells, while in others, it appears to promote these functions. We discuss the current state of the body of knowledge on the role of MARCKS in tumorigenesis, metastasis, and resistance to anti-cancer therapies, focusing on the molecular mechanisms by which MARCKS causes the phenotypic changes driving these phenomena in order to possibly understand the discrepancies in the experimental results found in the literature. We briefly consider future directions for investigations of MARCKS based on recent studies, including its role in Cancer Metastasis Rev (2017) 36:737–747 antineoplastic resistance and its potential as a biomarker and therapeutic target
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