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This version published online on November 13, 2003
Molecular Endocrinology, doi:10.1210/me.2003-0087
Molecular Endocrinology Vol. 0, No. 2003 200300871-
doi:10.1210/me.2003-0087
Copyright © 2003 by the Endocrine Society.
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Submitted on March 13, 2003
Accepted on November 4, 2003

PKC-{lambda} Knockout in Embryonic Stem Cells and Adipocytes Impairs Insulin-stimulated Glucose Transport

Gautam Bandyopadhyay1, Mary L. Standaert1, Mini P. Sajan1, Yoshinori Kanoh1, Atsushi Miura1, Uschi Braun1, Friederike Kruse1, Michael Leitges1, and Robert V. Farese1*

1 James A. Haley Veterans Hospital and University of South Florida College of Medicine, 13000 Bruce B. Downs Blvd., Tampa, FL, 33612, USA and Max-Planck Institute for Experimental Endocrinology, Feodor-Lynen Strasse 7, 30625 Hannover, Germany

* To whom correspondence should be addressed. E-mail: rfarese{at}hsc.usf.edu.

Atypical protein kinase C isoforms have been suggested to mediate insulin effects on glucose transport in adipocytes and other cells. To more rigorously test this hypothesis, we generated mouse embryonic stem (ES) cells and ES-derived adipocytes in which both atypical protein kinase C-{lambda} (PKC-{lambda}) alleles were knocked out by recombinant methods. Insulin activated PKC-{lambda} and stimulated glucose transport in wild-type (WT) PKC-{lambda}+/+, but not in knockout PKC-{lambda}-/-, ES cells. However, insulin-stimulated glucose transport was rescued by expression of WT PKC-{lambda} in PKC-{lambda}-/- ES cells. Surprisingly, insulin-induced increases in both PKC-{lambda} activity and glucose transport were dependent on activation of PYK2, the ERK pathway and phospholipase D (PLD), but independent of phosphatidylinositol 3-kinase (PI3K) in PKC-{lambda}+/+ ES cells. Interestingly, this dependency was completely reversed after differentiation of ES cells to adipocytes, i.e. insulin effects on PKC-{lambda} and glucose transport were dependent on PI3K, rather than PYK2/ERK/PLD. As in ES cells, insulin effects on glucose transport were absent in PKC-{lambda}-/- adipocytes, but rescued by expression of WT PKC-{lambda} in these adipocytes. Our findings suggest that insulin activates atypical PKCs and glucose transport in ES cells by a newly recognized PI 3-kinase-independent ERK/PLD-dependent pathway, and provide a compelling line of evidence suggesting that atypical PKCs are required for insulin-stimulated glucose transport, regardless of whether aPKCs are activated by PI3K-dependent or PI3K-independent mechanisms.
Key words: Adipocytes • Atypical PKC-{lambda} • Embryonic stem cells • Glucose transport • Insulin




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