Potential molecular mechanism for c-Src kinase-mediated regulation of intestinal cell migration.

Abstract

The ubiquitously expressed Src tyrosine kinases (c-Src, c-Yes, and c-Fyn) regulate intestinal cell growth and differentiation. Src activity is also elevated in the majority of malignant and premalignant tumors of the colon. The development of fibroblasts with the three ubiquitously expressed kinases deleted (SYF cells) has identified the role of Src proteins in the regulation of actin dynamics associated with increased cell migration and invasion. Despite this, unexpectedly nothing is known about the role of the individual Src kinases on intestinal cell cytoskeleton and/or cell migration. We have previously reported that villin, an epithelial cell-specific actin-modifying protein that regulates actin reorganization, cell morphology, cell migration, cell invasion, and apoptosis, is tyrosine-phosphorylated. In this report using the SYF cells reconstituted individually with c-Src, c-Yes, c-Fyn, and wild type or phosphorylation site mutants of villin, we demonstrate for the first time the absolute requirement for c-Src in villin-induced regulation of cell migration. The other major finding of our study is that contrary to previous reports, the nonreceptor tyrosine kinase, Jak3 (Janus kinase 3), does not regulate phosphorylation of villin or villin-induced cell migration and is, in fact, not expressed in intestinal epithelial cells. Further, we identify SHP-2 and PTP-PEST (protein-tyrosine phosphatase proline-, glutamate-, serine-, and threonine-rich sequence) as negative regulators of c-Src kinase and demonstrate a new function for these phosphatases in intestinal cell migration. Together, these data suggest that in colorectal carcinogenesis, elevation of c-Src or down-regulation of SHP-2 and/or PTP-PEST may promote cancer metastases and invasion by regulating villin-induced cell migration and cell invasion.

• Authors: Sijo Mathew, Sudeep P George, Yaohong Wang, Mohammad Rizwan Siddiqui, Kamalakkannan Srinivasan, Langzhu Tan, Seema Khurana
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 283 Issue 33 Pg. 22709-22 (Aug 15 2008) ISSN: 0021-9258 [Print] United States
• PMID: 18482983 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Cytoskeletal Proteins
• ezrin
• Protein-Tyrosine Kinases
• CSK Tyrosine-Protein Kinase
• JAK3 protein, human
• Janus Kinase 3
• src-Family Kinases
• CSK protein, human

Topics

• CSK Tyrosine-Protein Kinase
• Caco-2 Cells (physiology)
• Cell Line, Tumor
• Cell Movement (physiology)
• Cytoskeletal Proteins (metabolism)
• HeLa Cells
• Humans
• Janus Kinase 3 (metabolism)
• Neoplasm Invasiveness
• Phosphorylation
• Protein-Tyrosine Kinases (metabolism)
• src-Family Kinases