Vj. Fincham et al., V-SRC-INDUCED DEGRADATION OF FOCAL ADHESION KINASE DURING MORPHOLOGICAL TRANSFORMATION OF CHICKEN-EMBRYO FIBROBLASTS, Oncogene, 10(11), 1995, pp. 2247-2252
Morphological transformation of cells by the v-Src tyrosine kinase is
incompletely understood, However, it is independent of nuclear functio
ns and probably involves phosphorylation of targets associated with th
e cytoskeleton and focal adhesions, structures which tether the cytosk
eleton to the points of cell attachment. v-Src activity both stimulate
s tyrosine phosphorylation of a tyrosine kinase present in focal adhes
ions (focal adhesion kinase or pp125(FAK)) and disrupts focal adhesion
s, leading to cell rounding and detachment. However, pp125(FAK) is als
o phosphorylated on tyrosine as a result of integrin stimulation which
induces quite different biological consequences including the organis
ation of focal adhesions when cells spread on fibronectin (reviewed in
Schaller and Parsons, 1993). To address this paradox, we examined cha
nges in pp125(FAK) during activation and shut-off of temperature sensi
tive mutant v-Src proteins that induce varying degrees of transformati
on in chick embryo fibroblasts. An efficiently transforming v-Src muta
nt initially stimulated pp125(FAK) tyrosine phosphorylation, but induc
ed subsequent pp125(FAK) degradation prior to the onset of cell roundi
ng and detachment. v-Src mutants which are impaired in their ability t
o induce morphological transformation were much less efficient at indu
cing degradation of pp125(FAK). Moreover, cell spreading during restit
ution of normal morphology did not require detectable tyrosine phospho
rylation of pp125(FAK), or its potential substrate paxillin, suggestin
g that pp125(FAK) may function more in the turnover of focal adhesions
than in their assembly.