MON-251 - Effect of Corticotropin-Releasing Factor (CRF) on Insulin-Like Growth Factor-1 Receptor (IGF-1R) Signaling Pathways

Corticotropin-releasing factor (CRF) is a key neuropeptide that regulates the hypothalamic–pituitary–adrenal (HPA) axis and coordinates endocrine, autonomic, and behavioral responses to stress. Chronic activation of this system leads to sustained HPA axis dysregulation, a hallmark of stress-related psychiatric disorders, such as depression and anxiety, which are characterized by elevated CRF levels and increased expression of its receptor, CRF1R. These pathological conditions are associated with reduced circulating levels of insulin-like growth factor 1 (IGF-1) and decreased expression of its receptor, IGF-1R, which mediates mitogenic, metabolic, and survival signals primarily through the MAPK and PI3K/Akt signaling pathways. Although alterations in both CRF/CRF1R and IGF-1/IGF-1R signaling have been independently documented in stress-related disorders, the molecular mechanisms underlying the potential crosstalk between these systems remain largely unexplored. Elucidating these interactions is particularly relevant, given the central role of MAPK and PI3K/Akt signaling in neuronal plasticity, metabolism, and cell survival. In this study, we aimed to characterize the regulatory mechanisms by which CRF/CRF1R modulates IGF-1/IGF-1R–dependent activation of the MAPK and PI3K/Akt signaling pathways, providing mechanistic insight into how stress-related neuropeptide signaling may influence growth factor–mediated cellular responses. To address this, CHO-K1 cells transiently transfected with HA-hCRF1R were pre-stimulated with CRF and stimulated with IGF-1. Our results demonstrate that CRF, acting through CRF1R, triggers a regulatory mechanism that negatively modulates IGF-1 signaling by reducing IGF-1–induced phosphorylation of IGF-1R (Tyr1131), IRS-1 (Tyr632), Akt (Ser473), and ERK1/2 (Thr202/Tyr204). At the IGF-1R level, CRF increased serine phosphorylation, thereby promoting its negative regulation and facilitating β-arrestin 1 recruitment. Furthermore, CRF enhanced phosphorylation at Ser307 and Ser612 in IRS-1, two critical residues associated with the functional inhibition of this adaptor protein. Moreover, the CRF-mediated reduction in ERK1/2 activation was dependent on mTOR and JNK, which function as additional negative modulators of ERK1/2 activation. Finally, CRF-induced activation of the protein tyrosine phosphatase PTP1B (Tyr152) emerged as a key integrative mechanism due to its ability to dephosphorylate IGF-1R and IRS-1. Together, these findings identify a previously unrecognized molecular crosstalk between the CRF/CRF1R and IGF-1/IGF-1R signaling pathways and provide mechanistic insight into how stress-related neuropeptide signaling may impair growth factor–mediated cellular responses relevant to stress-associated neuropathologies.

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