Inhibition of protein kinase B (PKB) and PKCzeta mediates keratin K10-induced cell cycle arrest.
The intermediate filament cytoskeleton is composed of keratins in all epithelial cells and imparts mechanical integrity to these cells. However, beyond this shared function, the functional significance of the carefully regulated tissue- and differentiation-specific expression of the large keratin family of cytoskeletal proteins remains unclear. We recently demonstrated that expression of keratin K10 or K16 may regulate the phosphorylation of the retinoblastoma protein (pRb), inhibiting (K10) or stimulating (K16) cell proliferation (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 show that keratin K10 function as a negative modulator of cell cycle progression involves changes in the phosphoinositide 3-kinase (PI-3K) signal transduction pathway. Physical interaction of K10 with Akt (protein kinase B [PKB]) and atypical PKCzeta causes sequestration of these kinases within the cytoskeleton and inhibits their intracellular translocation. As a consequence, the expression of K10 impairs the activation of PKB and PKCzeta. We also demonstrate that this inhibition impedes pRb phosphorylation and reduces the expression of cyclins D1 and E. Functional and biochemical data also demonstrate that the interaction between K10 and these kinases involves the non-alpha-helical amino domain of K10 (NTerm). Together, these results suggest new and essential roles for the keratins as modulators of specific signal transduction pathways.
Paramio
J M
JM
Project on Cell and Molecular Biology and Gene Therapy, CIEMAT, E-28040 Madrid, Spain.
Segrelles
C
C
Ruiz
S
S
Jorcano
J L
JL
D000818:Animals; D002453:Cell Cycle / Q000187:drug effects*; D002454:Cell Differentiation; D002455:Cell Division; D019938:Cyclin D1 / Q000378:metabolism; D019927:Cyclin E / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D053550:Keratin-10; D007633:Keratins / Q000378:metabolism*; D051379:Mice; D008856:Microscopy, Fluorescence; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011485:Protein Binding; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D017346:Protein Serine-Threonine Kinases; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D051057:Proto-Oncogene Proteins c-akt; D016160:Retinoblastoma Protein / Q000378:metabolism; D015398:Signal Transduction; D013696:Temperature; D014162:Transfection; D014407:Tumor Cells, Cultured; D020798:Two-Hybrid System Techniques; D000099221:Protein Kinase C zeta
D019938:Cyclin D1; D019927:Cyclin E; D053550:Keratin-10; D007633:Keratins; D011493:Protein Kinase C; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D016160:Retinoblastoma Protein; D000099221:Protein Kinase C zeta; C507493:KRT10 protein, human; C507491:Krt10 protein, mouse; C494918:AKT1 protein, human