title: 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.affiliation: Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA.
authors.forename: Sijo
authors.initials: S
authors.lastname: Mathew
authors.forename: Sudeep P
authors.initials: SP
authors.lastname: George
authors.forename: Yaohong
authors.initials: Y
authors.lastname: Wang
authors.forename: Mohammad Rizwan
authors.initials: MR
authors.lastname: Siddiqui
authors.forename: Kamalakkannan
authors.initials: K
authors.lastname: Srinivasan
authors.forename: Langzhu
authors.initials: L
authors.lastname: Tan
authors.forename: Seema
authors.initials: S
authors.lastname: Khurana
mesh_terms: D000081247:CSK Tyrosine-Protein Kinase; D018938:Caco-2 Cells / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D003598:Cytoskeletal Proteins / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D053616:Janus Kinase 3 / Q000378:metabolism; D009361:Neoplasm Invasiveness; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D019061:src-Family Kinases; D000099149:Ezrin
chemical_list: D000081247:CSK Tyrosine-Protein Kinase; D003598:Cytoskeletal Proteins; D053616:Janus Kinase 3; D011505:Protein-Tyrosine Kinases; D019061:src-Family Kinases; D000099149:Ezrin; C507933:JAK3 protein, human; C000631346:CSK protein, human