title: HASF (C3orf58) is a novel ligand of the insulin-like growth factor 1 receptor.
abstract: We have recently shown that hypoxia and Akt-induced stem cell factor (HASF) protects the heart from ischemia-induced damage and promotes cardiomyocyte proliferation. While we have identified certain signaling pathways responsible for these protective effects, the receptor mediating these effects was unknown. Here, we undertook studies to identify the HASF receptor. A yeast two-hybrid screen identified a partial fragment of insulin-like growth factor 1 receptor (IGF1R) as a binding partner of HASF. Subsequent co-immunoprecipitation experiments showed that HASF bound to full-length IGF1R. Binding assays revealed a high affinity of HASF for IGF1R. The treatment of neonatal ventricular cardiomyocytes with HASF resulted in the phosphorylation of IGF1R and other proteins known to be involved in IGF1R-mediated signaling pathways. HASF-mediated ERK activation was abrogated by IGF1R pharmacological inhibitors and siRNAs that targeted IGF1R. However, siRNA-mediated knockdown of either IGF2R or the insulin receptor had no effect on HASF-induced cell signaling. Additionally, pharmacologic inhibition of IGF1R impeded HASF's ability to induce cardiomyocyte proliferation. Finally, we documented thatin vivodeletion of the IGF1R completely abolished the ability of HASF to promote cardiomyocyte proliferation in an overexpression mouse model providing further evidencein vivothat the IGF1R is the functional receptor for HASF.
authors.affiliation: Mandel Center for Hypertension and Atherosclerosis Research, Duke University Medical Center, Durham, NC, U.S.A.|Cardiovascular Research Center, Duke University Medical Center, Durham, NC, U.S.A.
authors.forename: Akshay
authors.initials: A
authors.lastname: Bareja
authors.affiliation: Mandel Center for Hypertension and Atherosclerosis Research, Duke University Medical Center, Durham, NC, U.S.A.|Cardiovascular Research Center, Duke University Medical Center, Durham, NC, U.S.A.
authors.forename: Conrad P
authors.initials: CP
authors.lastname: Hodgkinson
authors.affiliation: Mandel Center for Hypertension and Atherosclerosis Research, Duke University Medical Center, Durham, NC, U.S.A.|Cardiovascular Research Center, Duke University Medical Center, Durham, NC, U.S.A.
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Payne
authors.affiliation: Mandel Center for Hypertension and Atherosclerosis Research, Duke University Medical Center, Durham, NC, U.S.A.|Cardiovascular Research Center, Duke University Medical Center, Durham, NC, U.S.A.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Pratt
authors.affiliation: Mandel Center for Hypertension and Atherosclerosis Research, Duke University Medical Center, Durham, NC, U.S.A. victor.dzau@duke.edu.|Cardiovascular Research Center, Duke University Medical Center, Durham, NC, U.S.A.
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Dzau
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001665:Binding Sites; D049109:Cell Proliferation / Q000187:drug effects; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation; D061251:Primary Cell Culture; D011485:Protein Binding; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D017527:Receptor, IGF Type 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D020798:Two-Hybrid System Techniques
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; C532314:DIPK2A protein, human; D008024:Ligands; D008565:Membrane Proteins; C501177:NVP-AEW541; D011743:Pyrimidines; D011758:Pyrroles; D034741:RNA, Small Interfering; D017527:Receptor, IGF Type 2; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3
keywords: insulin-like growth factor; paracrine signaling; signaling