Membrane mobility and clustering of Integrin Associated Protein ( IAP, CD47)--major differences between mouse and man and implications for signaling.
Integrin Associated Protein ( IAP, CD47) is a ubiquitous integral membrane protein implicated in processes (in mice) that range from inhibiting clearance by phagocytes [Oldenborg et al., Science 2000; Gardai et al., Cell 2005] to neutrophil motility [Lindberg et al., Science 1996]. SIRPalpha is CD47's main receptor on phagocytes plus a number of other cell types, and SIRPalpha- CD47 interactions in clusters are believed to mediate signaling. However, considerable species differences in CD47 sequence as well as differences in CD47 extractability from mouse cells versus man motivate a characterization of mobility, clusterability, and kinetics under force of CD47-SIRPalpha. Despite similar levels of CD47 on red cells from mouse and man, we find an effective avidity of SIRPalpha- CD47 for mouse appears higher than for human. Both mouse and human CD47 show clustering by multivalent SIRPalpha complexes, but only mouse cells aggregate with CD47 concentrating at cell-cell contacts. This proves consistent with fluorescence imaged micro-deformation, which indicates near-complete mobility of CD47 on mouse cells compared to only about 30-40% mobility on normal human cells. To qualify the method, we also show that disrupting cellular F-actin dramatically increases the mobility of integral membrane proteins. Furthermore, atomic force microscopy probing of cell membranes with human SIRPalpha confirms the species-specific interactions and provides evidence of clustering and adhesion on short time scales, but it also shows surprisingly strong forces in detachment for a signaling complex. The results thus highlight major species differences in CD47-SIRPalpha interactions and CD47 integration, suggesting that signaling by CD47 in man may be qualitatively different from mouse.[1]References
- Membrane mobility and clustering of Integrin Associated Protein (IAP, CD47)--major differences between mouse and man and implications for signaling. Subramanian, S., Tsai, R., Sen, S., Dahl, K.N., Discher, D.E. Blood Cells Mol. Dis. (2006) [Pubmed]
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