Nerve Growth Factor-dependent Activation of the Small GTPase Rin

Spencer, Michael; Shao, Haipeng; Tucker, H. Michael; Andres, Douglas A.

doi:10.1074/jbc.m111400200

Cited by 46 publications

(72 citation statements)

References 65 publications

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“…Rit during development are consistent with Rit playing a role in neuronal development, that is, Rin is expressed only in the mature nervous system (Lee et al, 1996;Spencer et al, 2002b), whereas Rit is expressed in primary neurons and the developing brain (Lee et al, 1996;Spencer et al, 2002a).…”

mentioning

confidence: 56%

“…Rit and its most closely related proteins, Rin and RIC, constitute a branch of the Ras subfamily of small GTPases (Lee et al, 1996;Shao et al, 1999). Rin expression is restricted to postnatal and adult brain and retina (Lee et al, 1996;Spencer et al, 2002b). In contrast, Rit is temporally and spatially expressed in many tissues, including developing brain (Lee et al, 1996;Spencer et al, 2002a), which indicates a function for Rit during neuronal development (Spencer et al, 2002a) (this study).…”

Section: Rit and Neuronal Development/regenerationmentioning

confidence: 79%

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Rit promotes MEK-independent neurite branching in human neuroblastoma cells

Hynds

Spencer

Andres

et al. 2003

Journal of Cell Science

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Rit, by sequence homology, is a member of the Ras subfamily of small guanine triphosphatases (GTPases). In PC6 cells, Rit signals through pathways both common to and different from those activated by Ras to promote cell survival and neurite outgrowth. However, the specific morphological changes induced by Rit in human cells are not known. Here, we show in a human neuronal model that Rit increases neurite outgrowth and branching through MEK-dependent and MEK-independent signaling mechanisms, respectively. Adenoviral expression of wild-type or constitutively active Rit increased neurite initiation,elongation and branching on endogenous matrix or a purified laminin-1 substratum of SH-SY5Y cells as assessed using image analysis. This outgrowth was morphologically distinct from that promoted by constitutively active Ras or Raf (evidenced by increased branching and elongation). Constitutively active Rit increased phosphorylation of ERK 1/2, but not Akt, and the MEK inhibitor PD 098059 blocked constitutively active Rit-induced neurite initiation but not elongation or branching. These results suggest that Rit plays a key role in human neuronal development and regeneration through activating both known and as yet undefined signaling pathways.

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mentioning

confidence: 56%

Section: Rit and Neuronal Development/regenerationmentioning

confidence: 79%

Rit promotes MEK-independent neurite branching in human neuroblastoma cells

Hynds

Spencer

Andres

et al. 2003

Journal of Cell Science

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“…To investigate the potential mechanistic importance of Rem function during myoblast differentiation, we generated replication-defective adenovirus engineered to express either wild-type Rem or a control virus containing the Rem cDNA cloned in the reverse orientation. These adenoviruses express the GFP gene under the control of a separate promoter, allowing the direct observation of the efficiency of infection by following GFP expression (10,15). Rem overexpressing cells did not differ from control cells or uninfected cells in gross morphology or in their ability to differentiate into mature myotubes, suggesting that Rem does not control myogenic differentiation (Fig.…”

Section: Resultsmentioning

confidence: 99%

Regulation of voltage-gated calcium channel activity by the Rem and Rad GTPases

Finlin

Crump²,

Satin³

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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Rem, Rem2, Rad, and Gem͞Kir (RGK) represent a distinct GTPase family with largely unknown physiological functions. We report here that both Rem and Rad bind directly to Ca 2؉ channel ␤-subunits ( R em, Rem2, Rad, and Gem͞Kir (RGK) are members of a Ras-related GTPase subfamily (RGK family), with many unique characteristics that distinguish them from other members of the Ras superfamily (1-5). The common structure for all RGK proteins consists of a conserved Ras-related core domain, a series of nonconservative amino acid substitutions within regions known to be involved in guanine nucleotide binding and hydrolysis, a non-CAAX-containing C-terminal extension, and large N-terminal extensions relative to other Ras family proteins. The conservation of structural features within the RGK proteins suggests shared mechanisms of regulation and the control of common cellular signal transduction networks. However, RGK subfamily members differ from each other and from other Ras-related proteins in their putative effector (G2) domains, suggesting that they interact with distinct regulatory and effector proteins, and each exhibits distinct tissue-specific expression patterns (1-5). Thus, despite their conserved structural and biochemical properties, functional evidence to suggest a unified mechanism of action has been limited.In this study, we investigated the ability of Rem and Rad to regulate Ca 2ϩ channel activity. Our results demonstrate that, although both proteins have distinct effector interaction domains, they each bind directly to Ca V ␤ subunits and inhibit detectable ionic current expression from the native cardiac L type, but not from T type, Ca 2ϩ channels when coexpressed in human embryonic kidney (HEK)293 cells. The Rem protein is expressed in striated muscle cells, and we demonstrate that Rem inhibits L type Ca 2ϩ channel activity in differentiated C2C12 myotubes. Deletion analysis demonstrates that the C terminus of Rem plays an important role in Ca V ␤ subunit association and is necessary for regulation of channel activity. Taken together, these studies indicate that Rem functions as a potent regulator of L type Ca 2ϩ channel function in muscle and suggest that a conserved physiological role for the RGK GTPase gene family is the control of Ca 2ϩ channel activity via modulation of Ca V ␤ subunit function. Experimental ProceduresRNase Protection Assays and Cell Culture. C2C12DS and C2C12(E) mouse muscle myoblast cell lines were from Robert Krauss (Mount Sinai School of Medicine, New York) and were cultured and induced to differentiate as described (6). Primary mouse muscle cultures and MM14 cells were provided by

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“…Cell Lines and Transfections-PC6 cell is a subline of PC12 cells that produces neurites in response to NGF but grows as well isolated cells rather than in clumps and is suited to both biochemical and morphological analysis of signaling pathways (19,21,23). PC6 and COS cells were cultured in Dulbecco's modified Eagle's medium (DMEM, Invitrogen) supplemented with 10% fetal bovine serum (FBS) and 5% horse serum or 10% FBS, respectively.…”

Section: Methodsmentioning

confidence: 99%

“…Although our previous studies have demonstrated that the closely related Rit GTPase signals to a variety of Ras-responsive promoter elements, transforms NIH 3T3 cells to tumorigenicity, and activates the Ral exchange factor RGL3, Rin had little to no activity in these assays. Thus, Rin and Rit are likely to regulate distinct cellular functions, and characterization of Rin function remains incomplete (17)(18)(19). We have shown recently that Rin is activated following NGF stimulation of pheochromocytoma cells (19), and together with studies implicating Rin signaling in calcium-mediated neurite outgrowth (19,20), these data have led to the proposal that Rin signaling may play a pivotal role in regulating neuronal signaling pathways.…”

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confidence: 99%

Rin GTPase Couples Nerve Growth Factor Signaling to p38 and b-Raf/ERK Pathways to Promote Neuronal Differentiation

Shi

Han

Andres

2005

Journal of Biological Chemistry

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In neuronal precursor cells, the magnitude and longevity of mitogen-activated protein (MAP) kinase cascade activation contribute to the nature of the cellular response, differentiation, or proliferation. However, the mechanisms by which neurotrophins promote prolonged MAP kinase signaling are not well understood. Here we defined the Rin GTPase as a novel component of the regulatory machinery contributing to the selective integration of MAP kinase signaling and neuronal development. Rin is expressed exclusively in neurons and is activated by neurotrophin signaling, and loss-offunction analysis demonstrates that Rin makes an essential contribution to nerve growth factor (NGF)-mediated neuronal differentiation. Most surprisingly, although Rin was unable to stimulate MAP kinase activity in NIH 3T3 cells, it potently activated isoform-specific p38␣ MAP kinase signaling and weakly stimulated ERK signaling in pheochromocytoma (PC6) cells. This cell-type specificity is explained in part by the finding that Rin binds and stimulates b-Raf but does not activate c-Raf. Accordingly, selective down-regulation of Rin in PC6 cells suppressed neurotrophin-elicited activation of b-Raf and p38, without obvious effects on NGF-induced ERK activation. Moreover, the ability of NGF to promote neurite outgrowth was inhibited by Rin knockdown. Together, these observations establish Rin as a neuronal specific regulator of neurotrophin signaling, required to couple NGF stimulation to sustain activation of p38 MAP kinase and b-Raf signaling cascades required for neuronal development.Neurotrophin signaling is responsible for the regulation of a wide range of nerve cell functions, including differentiation, axonal and dendritic elongation, survival, and many aspects of neuronal activity (1). These diverse biological effects are mediated predominantly by the Trk family of receptor tyrosine kinases. Upon ligand binding, activated Trk receptors recruit adaptor proteins and activate Ras-related GTP-binding proteins and other effectors to modulate a diverse array of canonical signaling pathways (2). Among these cascades, both ERK 2 and p38 MAP kinase pathways have been shown to be essential for cellular proliferation and the acquisition and maintenance of a differentiated phenotype. A distinguishing feature of neurotrophin signaling is the sustained activation of ERK kinase activity (3). Previous studies have suggested that the longevity of MEK/ERK pathway activation (4, 5) is critical for neuronal differentiation in many systems, and Ras-like GTPases have emerged as key elements in these pathways (1). The Raf-MEK-ERK kinase cascade is implicated in the regulation of diverse biological processes, including both cellular proliferation and differentiation, and an important remaining issue is how integration of MAP kinase cascade signaling promotes distinct biological responses. However, although an extensive literature supports a role for prolonged MEK/ERK signaling in neuronal differentiation, inhibition of the sustained phase of ERK activation doe...

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Nerve Growth Factor-dependent Activation of the Small GTPase Rin

Cited by 46 publications

References 65 publications

Rit promotes MEK-independent neurite branching in human neuroblastoma cells

Rit promotes MEK-independent neurite branching in human neuroblastoma cells

Regulation of voltage-gated calcium channel activity by the Rem and Rad GTPases

Rin GTPase Couples Nerve Growth Factor Signaling to p38 and b-Raf/ERK Pathways to Promote Neuronal Differentiation

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