Signaling cross talk between growth hormone (GH) and insulin-like growth factor-I (IGF-I) in pancreatic islet β-cells.
Dysfunction and destruction of pancreatic islet β-cells is a hallmark of diabetes. Better understanding of cell signals regulating β-cell growth and antiapoptosis will allow development of therapeutic strategies for diabetes by preservation and expansion of β-cell mass. GH and IGF-I share a complicated physiological relationship and have both been implicated in β-cell function. GH and IGF-I exert their biological effects through binding to respective receptors (GHR and IGF-IR) and subsequently engaging downstream signaling pathways. However, their collaborative roles in modulation of β-cell mass and the underlying molecular mechanisms remain poorly understood. In this study, we demonstrate that cultured β-cells are appealing systems for investigating potential GH-IGF-I signaling cross talk. We uncover that GH specifically promotes formation of a protein complex containing GHR, Janus kinase 2 (a nonreceptor kinase coupled to GH/GHR signaling), and IGF-IR. More importantly, GH and IGF-I synergistically activate both signal transducer and activator of transcription 5 and Akt pathways. Concomitantly, β-cells proliferate more robustly and are better protected from serum deprivation-induced apoptosis when exposed to GH and IGF-I in combination vs. GH or IGF-I alone. The augmented proliferative effects by GH and IGF-I are confirmed in isolated islets. Taken together, our findings strongly suggest that there exists a novel signaling relationship between GH/GHR and IGF-I/IGF-IR systems in β-cells, i.e. IGF-IR may serve as a proximal component of GH/GHR signaling, contributing to enhancement of β-cell mass and function. In support of this, IGF-IR knockdown in β-cells resulted in the desensitization of acute GH-induced signal transducer and activator of transcription 5 activation.
Laboratory of Signal Transduction, Department of Obstetrics and Gynecology, St. Joseph’s Hospital and Medical Center, Phoenix, Arizona 85004, USA.
Fanxin
F
Ma
Zhe
Z
Wei
Chunwei
C
Shi
Yan
Y
Gan
Jia
J
Lu
Stuart J
SJ
Frank
James
J
Balducci
Yao
Y
Huang
D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D004789:Enzyme Activation; D055785:Gene Knockdown Techniques; D013006:Growth Hormone / Q000494:pharmacology / Q000502:physiology*; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology / Q000502:physiology*; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000502:physiology*; D053614:Janus Kinase 2 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D055503:Protein Multimerization; D034622:RNA Interference; D051381:Rats; D020239:Receptor Cross-Talk; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism*; D011986:Receptors, Somatotropin / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction
D011986:Receptors, Somatotropin; D050799:STAT5 Transcription Factor; C519530:insulin-like growth factor-1, mouse; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; D017526:Receptor, IGF Type 1; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2