Inhibition of protein kinase B (PKB) and PKC xi mediates keratin K10-induced cell cycle arrest

The intermediate filament cytoskeleton is composed of keratins in all epith elial cells and imparts mechanical integrity to these cells. However, beyon d this shared function, the functional significance of the carefully regula ted tissue- and differentiation-specific expression of the large keratin fa mily of cytoskeletal proteins remains unclear. We recently demonstrated tha t expression of keratin K10 or K16 may regulate the phosphorylation of the retinoblastoma protein (pRb), inhibiting (K10) or stimulating (K16) cell pr oliferation (J. M. Paramio, M. L. Casanova, C. Segrelles, S. Mittnacht, E. B. Lane, and J. L. Jorcano, Mol. Cell. Biol. 19:3086-3094, 1999). Here we s how that keratin K10 function as a negative modulator of cell cycle progres sion involves changes in the phosphoinositide 3-kinase (PI-3K) signal trans duction pathway. Physical interaction of K10 with Akt (protein kinase B [PK B]) and atypical PKC zeta causes sequestration of these kinases within the cytoskeleton and inhibits their intracellular translocation. As a consequen ce, the expression of K10 impairs the activation of PKB and PKC. We also de monstrate that this inhibition impedes pRb phosphorylation and reduces the expression of cyclins DI and E. Functional and biochemical data also demons trate that the interaction between K10 and these kinases involves the non-a lpha -helical amino domain of K10 (NTerm). Together, these results suggest new and essential roles for the keratins as modulators of specific signal t ransduction pathways.