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A more recent version of this article appeared on June 1, 2004
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Submitted on September 26, 2003
Revised on January 30, 2004
Accepted on February 26, 2004
1 subunit transmembrane domain regulates PI3K-dependent tyrosine phosphorylation of CAS
1 Department of Medical Biochemistry, and Microbiology, The Biomedical Center, Uppsala University, SE-751 23, Uppsala, Sweden
* Corresponding author. E-mail address: Annika.Armulik{at}cmb.ki.se.
Our previous studies on the transmembrane domain of human integrin subunits have shown that a conserved basic amino acid in both subunits of integrin heterodimers is positioned in the plasma membrane in the absence of interacting proteins (Armulik et al., 1999, JCB, 274: 37030-4). To investigate the possible functional role of the lipid-embedded lysine in the mouse integrin 
1 subunit, this amino acid was replaced with leucine, and the mutated 1 subunit (1AK756L) was stably expressed in 1-deficient GD25 cells. The extracellular domain of 1AK756L integrins possesses a competent conformation for ligand binding as determined by the ability to mediate cell adhesion, and by the presence of the mAb 9EG7 epitope. However, the spreading of GD25-1AK756L cells on fibronectin and laminin-1 was impaired, and the rate of migration of GD25-1AK756L cells on fibronectin was reduced compared with GD25-1A cells. Phosphorylation of tyrosines in focal adhesion kinase (FAK) and the Y416 in c-Src in response to 1AK756L-mediated adhesion was similar to that induced by wild-type 1. The tyrosine phosphorylation level of paxillin, a downstream target of FAK/Src, was unaffected by the 1 mutation while tyrosine phosphorylation of CAS was strongly reduced. The results demonstrate that CAS is a target for phosphorylation both by FAK-dependent and -independent pathways after integrin ligation. The latter pathway was inhibited by wortmannin and LY294002 implicating that it required an active PI3-kinase. Furthermore, the K756L mutation in the 1 subunit was found to interfere with 1-induced activation of Akt. The results from this study identify PI3K as an early component of a FAK-independent integrin signaling pathway triggered by the membrane proximal part of the 1 subunit.
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