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First published online January 26, 2005
doi: 10.1242/10.1242/jcs.01632
Research Article |
vß5 integrin-mediated phagocytosis of apoptotic cells
1 Department of Biochemistry and Molecular Biology, UMDNJ-New Jersey Medical School, 185 South Orange Avenue, Newark, NJ 07103, USA
2 Department of Neuro-Oncology and Molecular Genetics, MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA
* Author for correspondence (e-mail: birgera{at}umdnj.edu)
Accepted 4 November 2004
Efficient phagocytosis of apoptotic cells is crucial for many cellular processes. One of earliest signals to the phagocyte is the expression of phosphatidylserine (PS) on the outer surface of the apoptotic cell that provides a potent `eat-me' signal. Recognition of PS occurs either directly, via PS receptor (PS-R), or indirectly via 
vß5(3) integrin or Mer-family tyrosine kinases through the opsonizing proteins milk fat globule-EGF factor 8 protein (MFG-E8), or growth arrest specific factor-6 (Gas6), respectively. Because Mer and vß5 integrin share PS-dependent recognition signals, we investigated their post-receptor signaling cascades following receptor activation. Using a constitutively active form for Mer (CDMer) or Gas6 as a ligand to stimulate Mer, we found that Mer activation induced a post-receptor signaling cascade involving Src-mediated tyrosine phosphorylation of FAK on Tyr861, the recruitment of FAKTyr861 to the vß5 integrin, and increased formation of p130CAS/CrkII/Dock180 complex to activate Rac1. Coexpression of Mer with vß5 integrin had a synergistic effect on Rac1 activation, lamellipodial formation and the phagocytosis of apoptotic cells. Interestingly, Gas6 or CDMer failed to stimulate p130CAS tyrosine phosphorylation or phagocytosis in ß5-deficient CS-1 cells or in mutant ß5
C-expressing cells, suggesting that Mer is directionally and functionally linked to the integrin pathway. The present data indicate that receptors that recognize apoptotic cells in the context of PS functionally crosstalk to amplify intracellular signals to internalize apoptotic cells. Moreover, our data link another PS-dependent signal to the CrkII/Dock180/Rac1 module.
Key words: vß5 integrin, Mer tyrosine kinase, Rac1, Phagocytosis, Apoptotic cells
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