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J. Biol. Chem., Vol. 277, Issue 43, 40390-40396, October 25, 2002
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From the The survival and growth of epithelial cells
depend on adhesion to the extracellular matrix. Because epidermal
keratinocytes differentiate as they leave the basement membrane, an
adhesion signal may regulate the initiation of differentiation.
Phosphatidylinositol 3-kinase (PI3K) is a fundamental signaling
molecule that regulates the adhesion signal. Transfection of a dominant
negative form of PI3K into keratinocytes using an adenovirus vector
resulted in significant morphological changes comparable to
differentiation and the induction of differentiation markers, keratin
(K) 1 and K10. In turn, transfection with the constitutively active
form of PI3K almost completely abolished the induction of K1 and K10 by
differentiation in suspension cultures using
polyhydroxyethylmethacrylate-coated dishes. PI3K activity was lost in
suspension culture, except by cells bearing the constitutively active
form of PI3K. These data demonstrate that blockade of PI3K results in
differentiation and that activation of PI3K prevents differentiation.
Furthermore, expression of the dominant negative form of PI3K
significantly inhibited keratinocyte adhesion to the extracellular
matrix and reduced the surface expression of
Phosphatidylinositol 3-Kinase Is a Key Regulator of Early Phase
Differentiation in Keratinocytes*
§,,,,,
Department of Dermatology, Ehime University
School of Medicine, Ehime 791-0295 and the ¶ Department of
Biochemistry, The Institute of Medical Science, University of Tokyo,
Tokyo 113-8657, Japan
6 and
1 integrins in suspension culture. Moreover,
expression of the active form of PI3K restored the mRNA levels of
adhesion molecules that were reduced in suspension culture, including
3, 6, and 1 integrins,
BP180, and BP230. In conclusion, loss of PI3K activity results in
keratinocytes leaving the basement membrane and the initiation of a
"default" differentiation mechanism.
*
This work was supported by a grant for scientific research
from the Japanese Ministry of Education, Culture, Sports, Science, and
Technology.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
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