Regulation of mouse PECAM-1 tyrosine phosphorylation by the Src and Csk families of protein-tyrosine kinases

被引:88
作者
Cao, MY
Huber, M
Beauchemin, N
Famiglietti, J
Albelda, SM
Veillette, A
机构
[1] McGill Univ, Ctr Canc, Montreal, PQ H3G 1Y6, Canada
[2] McGill Univ, Dept Biochem, Montreal, PQ H3G 1Y6, Canada
[3] McGill Univ, Dept Med, Montreal, PQ H3G 1Y6, Canada
[4] McGill Univ, Dept Oncol, Montreal, PQ H3G 1Y6, Canada
[5] Montreal Gen Hosp, Dept Med, Montreal, PQ H3G 1A4, Canada
[6] Montreal Gen Hosp, Dept Oncol, Montreal, PQ H3G 1A4, Canada
[7] Univ Penn, Med Ctr, Dept Med, Philadelphia, PA 19014 USA
关键词
D O I
10.1074/jbc.273.25.15765
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
PECAM-1 is an adhesion molecule expressed on hemopoietic and endothelial cells. Recently, it was observed that PECAM-1 becomes tyrosine-phosphorylated in response to a variety of physiological stimuli. Furthermore, tyrosine-phosphorylated PECAM-1 was shown to associate with SHP-2, a Src homology 2 (SH2) domain-containing protein-tyrosine phosphatase expressed ubiquitously. In light of the significance of tyrosine protein phosphorylation as a regulatory mechanism, we wished to understand better the nature and impact of the protein-tyrosine kinases (PTKs) mediating PECAM-1 tyrosine phosphorylation. Through reconstitution experiments in COS-l cells, we determined that mouse PECAM-1 could be tyrosine-phosphorylated by Src-related PTKs and Csk-related PTKs, but not by other kinases such as Syk, Itk, and Pyk2. Using site-directed mutagenesis and peptide phosphorylation studies, we found that these PTKs were efficient at phosphorylating Tyr-686, but not Tyr-663, of PECARI-1. Src-related enzymes also phosphorylated mouse PECAM-1 at one or more yet to be identified sites. In other studies, we demonstrated that phosphorylation of PECAM-1 by Src or Csk family kinases was sufficient to trigger its association with SHP-2, Moreover, it was able to promote binding of PECAM-1 to SHP-1, a SHP-8-related protein-tyrosine phosphatase expressed in hemopoietic cells. Taken together, these findings indicated that the Src and Csk families of kinases are strong candidates for mediating tyrosine phosphorylation of PECAM-1 and triggering its association with SH2 domain-containing phosphatases under physiological circumstances.
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收藏
页码:15765 / 15772
页数:8
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