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Molecular and Cellular Biology, November 2001, p. 7449-7459, Vol. 21, No. 21
0270-7306/01/$04.00+0 DOI: 10.1128/MCB.21.21.7449-7459.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Inhibition of Protein Kinase B (PKB) and PKC
Mediates Keratin K10-Induced Cell Cycle Arrest
Jesus M.
Paramio,
Carmen
Segrelles,
Sergio
Ruiz, and
José L.
Jorcano*
Project on Cell and Molecular Biology and
Gene Therapy, CIEMAT, E-28040 Madrid, Spain
Received 21 February 2001/Returned for modification 17 April
2001/Accepted 18 July 2001
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
PKC
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 PKC
. 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-
-helical amino domain of K10 (NTerm).
Together, these results suggest new and essential roles for the
keratins as modulators of specific signal transduction pathways.
*
Corresponding author. Mailing address: Project on Cell
and Molecular Biology, CIEMAT, Av. Complutense 22, E-28040 Madrid, Spain. Phone: 34 91 3466598. Fax: 34 91 3466393. E-mail:
jl.jorcano{at}ciemat.es.
Molecular and Cellular Biology, November 2001, p. 7449-7459, Vol. 21, No. 21
0270-7306/01/$04.00+0 DOI: 10.1128/MCB.21.21.7449-7459.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
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