Figure 8
From: JNKs function as CDK4-activating kinases by phosphorylating CDK4 and p21
Model integrating the present observations with our previous analysis of the involvement of CDK7 and S130 phosphorylation of p21 in CDK4 activation.23 This model includes the evidence that p21 stabilizes cyclin D-CDK4 complexes but, at a higher stoichiometry of p21 binding, inhibits their activity.25 The model also considers that the T172 phosphorylation of CDK4 is particularly unstable, requiring a sustained activity of CDK4-activating kinases.23, 33 While CAK/CDK7 cannot phosphorylate CDK4 bound to unphosphorylated p21, JNKs and possibly p38α do it and thus are able to initiate the activation of p21-stabilized cyclin D1-CDK4 complexes by direct phosphorylation of CDK4 (arrow a). JNKs, p38α and ERK1/2 also phosphorylate p21 on S130 (arrow b) and possibly T57 (not represented), which could facilitate the CDK7-dependent phosphorylation of CDK423 (arrow c). The activation of CDK4 is then amplified and maintained by S130 phosphorylation of p21 by other active complexes of CDK4 (arrow d) and CDK2 (arrow e). As demonstrated by others,78, 79 S130 phosphorylation of p21 subsequently leads to increased degradation of p21 (arrow f), which facilitates CDK2 activation. Cooperation between JNKs and other signal transduction kinases (arrows a and b), CAK (arrow c) and cyclin-dependent kinases (arrows d and e) would thus initiate, amplify and maintain the activation of CDK4 to permit the passage through the R point. Green/red colors indicate a final positive/negative influence on R point passage.
