This is consistent with recent studies that suggest that Src and FAK act synergistically to control apoptosis (43, 49)

This is consistent with recent studies that suggest that Src and FAK act synergistically to control apoptosis (43, 49). Anchorage-independent growth. survival signaling, which, in turn, control apparently unique processes such as cell migration and anchorage-independent growth. This also highlights that dynamic regulation of actin and adhesions (which include the integrin matrix receptors) is critical to signaling output and biological responses. Elevated expression of the nonreceptor tyrosine kinases Src and focal adhesion kinase (FAK) correlates with malignancy potential and poor clinical prognosis in colon and breast tumors (2, 19, 20, 71, 90, 91). Recent studies monitoring focal adhesion dynamics in cells Norfloxacin (Norxacin) deficient for FAK and Src implicate Src and FAK as crucial mediators of integrin adhesion turnover that promote cell migration (97). Cells devoid of FAK exhibit impaired migration and have large peripheral focal adhesion structures (58), while cells lacking the three ubiquitous Src family members Src, Fyn, and Yes also demonstrate altered distribution of focal adhesions and impaired cell migration (64, 94). Src kinase activity is clearly necessary for focal adhesion turnover and Norfloxacin (Norxacin) cell motility, presumably by tyrosine phosphorylation of important focal adhesion substrates, such as FAK (22, 34). The extracellular regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) pathway is also important in regulating focal adhesion dynamics during cell motility (39, 63, 69, 99, 100), and it is likely that ERK/MAPK contributes to Src-induced focal adhesion turnover. Norfloxacin (Norxacin) We have recently reported that ERK/MAPK, which is usually recruited to focal adhesions following v-Src activation, is required for maximal activity of the protease calpain 2 promoting focal adhesion turnover and migration of v-Src-transformed cells (17, 35). ERK/MAPK-induced activation of calpain 2 is also required for epidermal growth factor-induced substrate deadhesion and cell motility (40, 41). The calpains are a highly conserved family of intracellular calcium-dependent proteases (for a review, see research 42). Calpain was first implicated in cell migration by studies utilizing pharmacological inhibition of calpain activity, which impaired retraction at Norfloxacin (Norxacin) the rear of the cell and decreased cell movement (55, 72). Further studies on calpain-null cells confirmed a role for calpain in regulating focal adhesion turnover, which is necessary for cell migration (29). Several components of the focal adhesion complex, including FAK (15, 16, 18, 25, 89, 95, 105), paxillin (103), talin (104), -actinin (85), and 3 integrin (30), are known substrates for calpain-mediated proteolysis, suggesting that calpain cleavage of one or more of these components contributes to focal adhesion disassembly. The relationship between Src and FAK activity and INHBA the precise mechanisms by which FAK promotes cell migration remain elusive. Several studies suggest that FAK promotes cell migration by activating multiple signaling pathways including Src family kinases and phosphatidylinositol (PI) 3-kinase or by phosphorylation of p130CAS, paxillin, or other focal adhesion substrates (21, 45, 79, 86, 88). FAK-dependent cell motility may also require its adaptor protein function, as it is usually reported that FAK expression, but not its kinase activity, is required for both platelet-derived growth factor- and epidermal growth factor-stimulated cell motility (86). A recent study exhibited that FAK can also take action upstream of calpain, suggesting a novel role by which FAK promotes focal adhesion turnover and cell motility (28). In this regard, we have also shown that FAK can act as an adaptor protein that permits the assembly of a complex consisting of calpain 2 and its upstream activator p42ERK, promoting calpain activity at the membrane (17). FAK also plays a role in suppressing cell apoptosis, particularly in response to cell detachment (anoikis) (5, 31, Norfloxacin (Norxacin) 38, 54, 73, 101). Indeed, a previous study suggested that FAK may transmit extracellular matrix (ECM)-derived survival signals that suppress p53-mediated apoptosis (57). However, the upstream mechanisms that regulate FAK-mediated survival.