Selected glimpses into the activation and function of Src kinase

Abstract

Since the discovery of the v-src and c-src genes and their products, much progress has been made in the elucidation of the structure, regulation, localization, and function of the Src protein. Src is a non-receptor protein tyrosine kinase that transduces signals that are involved in the control of a variety of cellular processes such as proliferation, di erentiation, motility, and adhesion. Src is normally maintained in an inactive state, but can be activated transiently during cellular events such as mitosis, or constitutively by abnormal events such as mutation (i.e. v-Src and some human cancers). Activation of Src occurs as a result of disruption of the negative regulatory processes that normally suppress Src activity, and understanding the various mechanisms behind Src activation has been a target of intense study. Src associates with cellular membranes, in particular the plasma membrane, and endosomal membranes. Studies indicate that the di erent subcellular localizations of Src could be important for the regulation of speci®c cellular processes such as mitogenesis, cytoskeletal organization, and/or membrane tra cking. This review will discuss the history behind the discovery and initial characterization of Src and the regulatory mechanisms of Src activation, in particular, regulation by modi®cation of the carboxyterminal regulatory tyrosine by phosphatases and kinases. Its focus will then turn to the di erent subcellular localizations of Src and the possible roles of nuclear and perinuclear targets of Src. Finally, a brief section will review some of our present knowledge regarding Src involvement in human cancers. Oncogene (2000) 19, 5620 ± 5635.

Cbl-c suppresses v-Src-induced transformation through ubiquitin-dependent protein degradation

“…These data suggest that Cbl-c binds to phosphorylated Src primarily through the TKB domain. A phosphorylation-independent interaction between the SH3 domain of Src and a proline-rich region of Cbl-c may be involved in the binding of Src and Cbl-c. Tyr419 and Tyr530 of human Src (Tyr416 and Tyr527 of chicken Src, respectively) are major phosphorylation sites of Src (Bjorge et al, 2000). Tyr419 is highly conserved among Src family members, and the flanking amino-acid sequence confirms to the consensus Cbl docking site (D (D/N) xpYxxxP) (Lupher et al, 1997).…”

“…c-Src is a nonreceptor-type protein tyrosine kinase that is important for various mitogenic signalings and has been implicated in a variety of cancers. v-Src activates a number of signaling proteins and leads to transformation (Bjorge et al, 2000). Constitutive activation of signal transducers and activators of transcription 3 (STAT3), phosphatidylinositol 3-kinase (PI3-K)/Akt, and Ras/mitogen-activated protein kinase (MAPK) was observed in v-Src-transformed cells (Odajima et al, 2000).…”

The rat tyrosine phosphatase η increases cell adhesion by activating c-Src through dephosphorylation of its inhibitory phosphotyrosine residue

“…Consequent to this intramolecular binding, c-Src remains in an inactive conformation and does not exert tyrosine kinase activity (Roussel et al, 1991;Xu et al, 1997). Several tyrosine phosphatases can activate c-Src by dephosphorylating phosphotyrosine 527 (Bjorge et al, 2000), thereby counteracting the activity of c-Src terminal kinase (csk) on this aminoacid (Nada et al, 1991). Conversely, dephosphorylation of the second regulatory site of c-Src, Tyr 416, leads to inhibition of c-Src tyrosine kinase activity (Bjorge et al, 2000).…”

Protein-tyrosine Phosphatase PTPD1 Regulates Focal Adhesion Kinase Autophosphorylation and Cell Migration

“…The epithelialmesenchymal transition depends on EGF activation and Srcdependent signaling and is associated with increased cell motility (3,(33)(34)(35)(36). Since PTPD1-Src up-regulates the EGF pathway, we suspected that PTPD1 might promote cell motility.…”