Molecular cloning of mammalian Spred-3 which suppresses tyrosine kinase-mediated Erk activation

Kato, Reiko; Nonami, Atsushi; Taketomi, Takaharu; Wakioka, Toru; Kuroiwa, Asato; Matsuda, Yoichi; Yoshimura, Akihiko

doi:10.1016/s0006-291x(03)00259-6

Cited by 107 publications

(141 citation statements)

References 25 publications

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“…Therefore, we speculated that a deficiency of Spred in hepatocytes causes hyperproliferative cell, leading to tumorigenicity. However, neither Spred-1 null mice nor Spred-2 null mice developed any tumors, which was probably due to the redundancy in the physiological function of Spred-1 and -2 because Spred-1 and -2 are coexpressed in various organs and have similar effect on ERK activity (Wakioka et al, 2001;Kato et al, 2003). In our study, expression levels of Spred-1 and -2 were simultaneously decreased in identical HCC tumors at a high rate (22/27:68%).…”

Section: Discussioncontrasting

confidence: 53%

Spreds, inhibitors of the Ras/ERK signal transduction, are dysregulated in human hepatocellular carcinoma and linked to the malignant phenotype of tumors

et al. 2006

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Aberrant activation of the Ras/Raf-1/extracellular-regulated kinase (ERK) pathway has been shown to be involved in the progression of human hepatocellular carcinoma (HCC). However, the mechanism of dysregulation of ERK activation is poorly understood. Recently, we identified Sprouty-related protein with Ena/vasodilator-stimulated phosphoprotein homology-1 domain (Spred) as a physiological inhibitor of the Ras/Raf-1/ ERK pathway. In this study, we found that the expression levels of Spred-1 and -2 in human HCC tissue were frequently decreased, comparing with those in adjacent non-tumorous tissue. Moreover, Spred expression levels in HCC tissue were inversely correlated with the incidence of tumor invasion and metastasis. Forced expression of Spred-1 inhibited HCC cell proliferation in vitro and in vivo, which was associated with reduced ERK activation. Spred-1 overexpression also reduced the secretion of matrix metalloproteinase-9 (MMP-9) and MMP-2, which play important roles in tumor invasion and metastasis. In addition, Spred-1 inhibited growth factor-mediated HCC cell motility. These data indicate that the reduction of Spred expression in HCC is one of the causes of the acquisition of malignant features. Thus, Spred could be not only a novel prognostic factor but also a new therapeutic target for human HCC.

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Section: Discussioncontrasting

confidence: 53%

Spreds, inhibitors of the Ras/ERK signal transduction, are dysregulated in human hepatocellular carcinoma and linked to the malignant phenotype of tumors

et al. 2006

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“…SPRED1 has been shown to be expressed predominantly in the brain (21,26) and to be enriched in the central nervous system, where it mediates cortical development, neural stem cell proliferation, and vesicular trafficking (26,37). Recently, it has been shown that germ line loss-of-function mutations of SPRED1 cause the neurofibromatosis type 1-like Legius syndrome, associated with café-au-lait spots, facial abnormalities, and behavioral and learning problems (31,(33)(34)(35).…”

Section: Discussionmentioning

confidence: 99%

“…Ets factors) and other target proteins (19,20). So far, three mammalian SPRED isoforms were described, and additional splice variants may exist (21,22). SPRED2 contains an N-terminal EVH1 domain, a central c-Kitbinding domain (KBD), and a C-terminal cysteine-rich Sprouty-like (SPR) domain (21,23).…”

mentioning

confidence: 99%

“…So far, three mammalian SPRED isoforms were described, and additional splice variants may exist (21,22). SPRED2 contains an N-terminal EVH1 domain, a central c-Kitbinding domain (KBD), and a C-terminal cysteine-rich Sprouty-like (SPR) domain (21,23). Both EVH1 and SPR domains are required for efficient suppression of MAPK signaling because deletion mutants lacking either the EVH1 or the SPR domain were unable to block growth factor-induced ERK activation (24).…”

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confidence: 99%

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Identification of SPRED2 (Sprouty-related Protein with EVH1 Domain 2) as a Negative Regulator of the Hypothalamic-Pituitary-Adrenal Axis

Ullrich

Bundschu

Benz

et al. 2011

Journal of Biological Chemistry

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Sprouty-related proteins with EVH1 (enabled/vasodilatorstimulated phosphoprotein homology 1) domain (SPREDs) are inhibitors of MAPK signaling. To elucidate SPRED2 in vivo function, we characterized body homeostasis in SPRED2 ؊/؊ mice. They showed a doubled daily water uptake, induced by elevated serum osmolality, originating from increased blood salt load. Accordingly, serum aldosterone was doubled, accompanied by augmented adrenal aldosterone synthase (AS) expression. Surprisingly, serum vasopressin (AVP) was unaltered, and, as evidenced by halved angiotensin II (Ang II) levels, the renin angiotensin system (RAS) was down-regulated. Adrenocorticotropic hormone (ACTH) was significantly elevated in SPRED2 ؊/؊ mice, together with its secretagogue corticotropinreleasing hormone (CRH) and its downstream target corticosterone. ERK phosphorylation in brains was augmented, and hypothalamic CRH mRNA levels were elevated, both contributing to the increased CRH release. Our data were supported by CRH promoter reporter assays in hypothalamic mHypoE-44 cells, revealing a SPRED-dependent inhibition of Ets (ERK/Etwenty-six)-dependent transcription. Furthermore, SPRED suppressed CRH production in these cells. In conclusion, our study suggests that SPRED2 deficiency leads to an increased MAPK signaling, which results in an augmented CRH promoter activity. The subsequent CRH overproduction causes an up-regulation of downstream hypothalamic-pituitary-adrenal (HPA) hormone secretion. This constitutes a possible trigger for the observed compulsive grooming in SPRED2 ؊/؊ mice and may, together with hyperplasia of aldosterone-producing cells, contribute to the hyperaldosteronism and homeostatic imbalances.

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“…Members of Sprouty family like Sprouty 2 have been identified to suppress Ras-ERK cascades through Src-induced phosphorylation at its Tyr-55 residue [15,16] . Spred, the Sprouty-related protein, was also found as a negative regulator of ERK pathway and to be upregulated directly by tyrosine kinases [17] . Our data also showed that inhibiting Src family tyrosine kinase activity with PP2 could effectively attenuate the ERK phosphorylation elicited by post-ischemia recovery, and ERK activation with a peak or distinct rebound usually occurred when Src kinase was activated mildly.…”

Section: Discussionmentioning

confidence: 99%

N-methyl-D-aspartate receptors mediate diphosphorylation of extracellular signal-regulated kinases through Src family tyrosine kinases and Ca2+/calmodulin-dependent protein kinase II in rat hippocampus after cerebral ischemia

Guo

2007

Neurosci. Bull.

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Objective: Extracellular signal-regulated kinases (ERKs) can be activated by calcium signals. In this study, we investigated whether calcium-dependent kinases were involved in ERKs cascade activation after global cerebral ischemia. Methods Cerebral ischemia was induced by four-vessel occlusion, and the calcium-dependent proteins were detected by immunoblot. Results Lethal-simulated ischemia significantly resulted in ERKs activation in N-methyl-D-aspartate (NMDA) receptor-dependent manner, accompanying with differential upregulation of Src kinase and Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) activities. With the inhibition of Src family tyrosine kinases or CaMKII by administration of PP2 or KN62, the phosphorylation of ERKs was impaired dramatically during post-ischemia recovery. However, ischemic challenge also repressed ERKs activity when Src kinase was excessively activated. Conclusions Src family tyrosine kinases and CaMKII might be involved in the activation of ERKs mediated by NMDA receptor in response to acute ischemic stimuli in vivo, but the intense activation of Src kinase resulted from ischemia may play a reverse role in the ERKs cascade.

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Molecular cloning of mammalian Spred-3 which suppresses tyrosine kinase-mediated Erk activation

Cited by 107 publications

References 25 publications

Spreds, inhibitors of the Ras/ERK signal transduction, are dysregulated in human hepatocellular carcinoma and linked to the malignant phenotype of tumors

Spreds, inhibitors of the Ras/ERK signal transduction, are dysregulated in human hepatocellular carcinoma and linked to the malignant phenotype of tumors

Identification of SPRED2 (Sprouty-related Protein with EVH1 Domain 2) as a Negative Regulator of the Hypothalamic-Pituitary-Adrenal Axis

N-methyl-D-aspartate receptors mediate diphosphorylation of extracellular signal-regulated kinases through Src family tyrosine kinases and Ca2+/calmodulin-dependent protein kinase II in rat hippocampus after cerebral ischemia

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