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C terminus of RGS-GAIP-interacting protein conveys neuropilin-1-mediated signaling during angiogenesis

Ling Wang^*,, Debabrata Mukhopadhyay^,1,2 and Xiaolei Xu^*,1,2

^* Department of Biochemistry and Molecular Biology,

Mayo Clinic Cancer Center, Mayo Clinic College of Medicine, Rochester, Minnesota, USA

¹Correspondence: D. M., Department Biochemistry and Molecular Biology, Gugg 1401A, Mayo Clinic College of Medicine, 200 First St. SW, Rochester, MN 55905. E-mail: mukhopadhyay.debabrata{at}mayo.edu; X. X., Department Biochemistry and Molecular Biology, Gugg 1701C, Mayo Clinic College of Medicine, 200 First St. SW, Rochester, MN 55905, USA. E-mail: xu.xiaolei{at}mayo.edu

ABSTRACT

Initially, it was thought that there was no intracellular signaling mediated by NRP-1 alone in response to its ligands. However, the emerging data from our group as well as others suggest that the signaling through NRP-1 actually promotes angiogenesis and is mediated through its C-terminal domain and downstream molecules such as phosphoinositide 3-kinase. Hence, understanding the signal transduction pathways mediated by NRP-1 and identification of its downstream molecules are of importance. By using both in vivo zebrafish model and in vitro tissue culture system, we have shown that the C-terminal three amino acids of NRP-1 (SEA-COOH) are required for NRP-1-mediated angiogenesis. Furthermore, knocking down of RGS-GAIP-interacting protein C terminus (GIPC) in zebrafish, which is associated with C-terminal domain of NRP-1, exhibits similar vasculature phenotypes to those from NRP-1 null. Specific and effective silencing of GIPC in vascular endothelium results in inhibition of NRP-1-mediated migration. In both cases as described, PDZ domain of GIPC is responsible for its function. Taken together, our data suggest a novel role of GIPC in angiogenesis and vessel formation and also support our hypothesis that NRP-1 can facilitate downstream signaling to promote angiogenesis through GIPC.—Wang, L., Mukhopadhyay, D., Xu, X. C terminus of RGS-GAIP-interacting protein conveys neuropilin-1-mediated signaling during angiogenesis.

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