Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rho GTPases are important regulators for cell dynamics. They are activated by guanine nucleotide exchange factors and inactivated by GTPase-activating proteins (GAPs). We recently identified a novel RhoGAP, BPGAP1, that uses the BNIP-2 and Cdc42GAP homology (BCH) domain, RhoGAP domain and proline-rich region to regulate cell morphology and migration. To further explore its roles in intracellular signaling, we employed protein precipitations and matrix-assisted laser desorption/ionization mass-spectrometry and identified EEN/endophilin II as a novel partner of BPGAP1. EEN is a member of the endocytic endophilin family but its function in regulating endocytosis remains unclear. Pull-down and co-immunoprecipitation studies with deletion mutants confirmed that EEN interacted directly with BPGAP1 via its Src homology 3 (SH3) domain binding to the proline-rich region 182-PPPRPPLP-189 of BPGAP1, with prolines 184 and 186 being indispensable for this interaction. Overexpression of EEN or BPGAP1 alone induced EGF-stimulated receptor endocytosis and ERK1/2 phosphorylation. These processes were further enhanced when EEN was present together with the wildtype but not with the non-interactive proline mutant of BPGAP1. However, EEN lacking the SH3 domain served as a dominant negative mutant that completely inhibited these effects. Furthermore, BPGAP1 with a catalytically inactive GAP domain also blocked the effect of EEN and/or BPGAP1 in EGF receptor endocytosis and concomitantly reduced their level of augmentation for ERK1/2 phosphorylation. Our findings reveal a concomitant activation of endocytosis and ERK signaling by BPGAP1 via the coupling of its proline-rich region, which targets EEN and its functional GAP domain. BPGAP1 could therefore provide an important link between cytoskeletal network, endocytic trafficking and Ras/MAPK signaling.
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PMID:Activation of EGF receptor endocytosis and ERK1/2 signaling by BPGAP1 requires direct interaction with EEN/endophilin II and a functional RhoGAP domain. 1594 98

BPGAP1 is a Rho GTPase-activating protein (RhoGAP) that regulates cell morphogenesis, cell migration, and ERK signaling by the concerted action of its proline-rich region (PRR), RhoGAP domain, and the BNIP-2 and Cdc42GAP homology (BCH) domain. Although multiple cellular targets for the PRR and RhoGAP have been identified, and their functions delineated, the mechanism by which the BCH domain regulates functions of BPGAP1 remains unclear. Here we show that its BCH domain induced robust ERK activation leading to PC12 cell differentiation by targeting specifically to K-Ras. Such stimulatory effect was inhibited, however, by both dominant-negative mutants of Mek2 (Mek2-K101A) and K-Ras (K-Ras-S17N) and also by the small G-protein GDP dissociation stimulator (SmgGDS). Consequently SmgGDS knockdown released this inhibition and resulted in a superinduction of K-Ras activation and PC12 differentiation mediated by BCH domain. These results demonstrate the versatility of the BCH domain of BPGAP1 in regulating ERK signaling by involving K-Ras and SmgGDS and support the unique role of BPGAP1 as a dual regulator for Ras and Rho signaling in cell morphogenesis and differentiation.
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PMID:SmgGDS antagonizes BPGAP1-induced Ras/ERK activation and neuritogenesis in PC12 cell differentiation. 2315 2

Simultaneous hyperactivation of stress-activated protein kinase/c-Jun N-terminal protein kinase (SAPK/JNK) and mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK/ERK) signaling cascades has been reported in carcinogenesis. However, how they are integrated to promote oncogenesis remains unknown. By analyzing breast invasive carcinoma database (The Cancer Genome Altas), we found that the mRNA expression levels of both JNK1 and ERK2 are positively correlated with the mRNA level of EEA1, an endosome associated protein, indicating the potential JNK/ERK crosstalk at endosome. Unbiased screen of different endosome-associated Rab GTPases reveals that late endosome serves as a unique platform to integrate JNK/ERK signaling. Furthermore, we identify that BPGAP1 (a BCH domain-containing, Cdc42GAP-like Rho GTPase-activating protein) promotes MEK partner 1 (MP1)-induced ERK activation on late endosome through scaffolding MP1/MEK1 complex. This regulatory function requires phosphorylation of BPGAP1 by JNK at its C terminal tail (Ser424) to unlock its autoinhibitory conformation. Consequently, phosphorylated BPGAP1 facilitates endosomal ERK signaling transduction to the nucleus, driving cell proliferation and transformation via the ERK-Myc-CyclinA axis. BPGAP1 therefore provides a crucial spatiotemporal checkpoint where JNK and MP1/MEK1 work in concert to regulate endosomal and nuclear ERK signaling in cell proliferation control.
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PMID:BPGAP1 spatially integrates JNK/ERK signaling crosstalk in oncogenesis. 2809 72