RGD Reference Report - Pituitary adenylate cyclase-activating polypeptide 38-mediated Rin activation requires Src and contributes to the regulation of HSP27 signaling during neuronal differentiation.

General

Pituitary adenylate cyclase-activating polypeptide 38-mediated Rin activation requires Src and contributes to the regulation of HSP27 signaling during neuronal differentiation.
Authors:	Shi, GX Jin, L Andres, DA
Citation:	Shi GX, etal., Mol Cell Biol. 2008 Aug;28(16):4940-51. Epub 2008 Jun 9.
RGD ID:	2325271
Pubmed:	PMID:18541665 (View Abstract at PubMed)
PMCID:	PMC2519709 (View Article at PubMed Central)
DOI:	DOI:10.1128/MCB.02193-07 (Journal Full-text)
Pituitary adenylate cyclase-activating polypeptide 38 (PACAP38) is a potent neuropeptide that acts through G-protein-coupled receptors. While it is well established that PACAP mediates both neurotrophic and neurodevelopmental effects, the signaling cascades that underlie these diverse actions remain incompletely characterized. Here we show that the Ras-related Rin GTP-binding protein, a GTPase that is expressed predominantly in neurons, is regulated by PACAP38 signaling, and loss-of-function analysis demonstrates that Rin makes an essential contribution to PACAP38-mediated pheochromocytoma cell differentiation. Rin is activated following stimulation of both Gsalpha and Gialpha cascades but does not rely upon cyclic AMP (cAMP)-, Ca(2+)-, or Epac-dependent signaling pathways. Instead, Rin is activated in a Src kinase-dependent manner. Surprisingly, Rin knockdown significantly inhibits PACAP38-mediated neurite outgrowth, without affecting mitogen-activated protein kinase signaling cascades. Instead, Rin loss attenuates PACAP38-mediated HSP27 activation by disrupting a cAMP-protein kinase A cascade. RNA interference-mediated HSP27 silencing suppresses both PACAP38- and Rin-mediated neurite outgrowth, while expression of a constitutively active Rin mutant increases both HSP27 protein and phospho-HSP27 levels, supporting a role for Rin-HSP27 signaling in neuronal differentiation. Together, these observations identify an unsuspected role for Rin in neuronal PACAP signaling and establish a novel Galpha-Src-Rin-HSP27 signal transduction pathway as a critical element in PACAP38-mediated neuronal differentiation signaling.

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Biological Process

Only show annotations with direct experimental evidence (0 objects hidden)

Term	Qualifier	Evidence	With	Reference	Notes	Source	Original Reference(s)
adenylate cyclase-activating G protein-coupled receptor signaling pathway	involved_in	IDA		2325271	PMID:18541665	BHF-UCL
adenylate cyclase-activating G protein-coupled receptor signaling pathway	involved_in	IMP		2325271	PMID:18541665	BHF-UCL
positive regulation of neuron projection development	involved_in	IGI	UniProtKB:P42930	2325271	PMID:18541665	ParkinsonsUK-UCL
positive regulation of neuron projection development	involved_in	IGI	UniProtKB:Q5BJQ5	2325271	PMID:18541665	ParkinsonsUK-UCL
positive regulation of neuron projection development		IDA		2325271		RGD
positive regulation of neuron projection development	involved_in	IGI	UniProtKB:P13589	2325271; 2325271	PMID:18541665	ParkinsonsUK-UCL
positive regulation of small GTPase mediated signal transduction	involved_in	IMP		2325271	PMID:18541665	ParkinsonsUK-UCL
regulation of protein phosphorylation	involved_in	IGI	UniProtKB:Q5BJQ5	2325271	PMID:18541665	ParkinsonsUK-UCL
regulation of protein phosphorylation	involved_in	IGI	UniProtKB:P13589	2325271	PMID:18541665	ParkinsonsUK-UCL

Objects Annotated

Genes (Rattus norvegicus)

Adcyap1 (adenylate cyclase activating polypeptide 1)

Adcyap1r1 (ADCYAP receptor type I)

Hspb1 (heat shock protein family B (small) member 1)

Rit2 (Ras-like without CAAX 2)

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Pituitary adenylate cyclase-activating polypeptide 38-mediated Rin activation requires Src and contributes to the regulation of HSP27 signaling during neuronal differentiation.