title: Interaction of the metalloprotease disintegrins MDC9 and MDC15 with two SH3 domain-containing proteins, endophilin I and SH3PX1.
abstract: Metalloprotease disintegrins (a disintegrin and metalloprotease (ADAM) and metalloprotease, disintegrin, cysteine-rich proteins (MDC)) are a family of membrane-anchored glycoproteins that function in diverse biological processes, including fertilization, neurogenesis, myogenesis, and ectodomain processing of cytokines and other proteins. The cytoplasmic domains of ADAMs often include putative signaling motifs, such as proline-rich SH3 ligand domains, suggesting that interactions with cytoplasmic proteins may affect metalloprotease disintegrin function. Here we report that two SH3 domain-containing proteins, endophilin I (SH3GL2, SH3p4) and a novel SH3 domain- and phox homology (PX) domain-containing protein, termed SH3PX1, can interact with the cytoplasmic domains of the metalloprotease disintegrins MDC9 and MDC15. These interactions were initially identified in a yeast two-hybrid screen and then confirmed using bacterial fusion proteins and co-immunoprecipitations from eukaryotic cells expressing both binding partners. SH3PX1 and endophilin I both preferentially bind the precursor but not the processed form of MDC9 and MDC15 in COS-7 cells. Since rat endophilin I is thought to play a role in synaptic vesicle endocytosis and SH3PX1 has sequence similarity to sorting nexins in yeast, we propose that endophilin I and SH3PX1 may have a role in regulating the function of MDC9 and MDC15 by influencing their intracellular processing, transport, or final subcellular localization.
authors.affiliation: Cellular Biochemistry Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
authors.forename: L
authors.initials: L
authors.lastname: Howard
authors.forename: K K
authors.initials: KK
authors.lastname: Nelson
authors.forename: R A
authors.initials: RA
authors.lastname: Maciewicz
authors.forename: C P
authors.initials: CP
authors.lastname: Blobel
mesh_terms: D051722:ADAM Proteins; D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D016564:Amyloid beta-Protein Precursor; D000818:Animals; D019556:COS Cells; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002451:Cell Compartmentation; D003001:Cloning, Molecular; D003593:Cytoplasm / Q000737:chemistry; D019483:Disintegrins / Q000235:genetics / Q000378:metabolism*; D005057:Eukaryotic Cells / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D011392:Proline; D058255:Protease Nexins; D011485:Protein Binding; D011498:Protein Precursors / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D011956:Receptors, Cell Surface; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D017422:Sequence Analysis, DNA; D058305:Sorting Nexins; D020798:Two-Hybrid System Techniques; D033921:Vesicular Transport Proteins; D018909:src Homology Domains
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016564:Amyloid beta-Protein Precursor; D002352:Carrier Proteins; D019483:Disintegrins; D008565:Membrane Proteins; D058255:Protease Nexins; D011498:Protein Precursors; D011956:Receptors, Cell Surface; D011993:Recombinant Fusion Proteins; C107640:SH3GL2 protein, human; C400533:SNX9 protein, human; C498434:Sh3gl2 protein, mouse; D058305:Sorting Nexins; D033921:Vesicular Transport Proteins; D011392:Proline; D051722:ADAM Proteins; C098660:ADAM15 protein, human; C098339:ADAM9 protein, human; C490902:Adam15 protein, mouse; C490901:Adam15 protein, rat; C498316:Adam9 protein, mouse; D008666:Metalloendopeptidases