scholarly journals p27Kip1 Inhibition of GRB2-SOS Formation Can Regulate Ras Activation

2003 ◽  
Vol 23 (11) ◽  
pp. 3735-3752 ◽  
Author(s):  
Stephanie J. Moeller ◽  
Elizabeth D. Head ◽  
Robert J. Sheaff
Keyword(s):  
Human Cancer ◽  
Growth Factor Receptor ◽  
Mitogen Activated Protein Kinase ◽  
Control Mechanisms ◽  
Nucleotide Exchange ◽  
Restriction Point ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factor ◽  
Ras Activation ◽  
Mitogen Activated Protein

ABSTRACT p27Kip1 (p27) is often inappropriately downregulated in aggressive human cancers. Although p27 can inhibit cyclin-dependent kinases (CDKs), low p27 does not always correlate with increased CDK activity. Furthermore, cells derived from p27−/− mice respond to antimitogens, maintain restriction point control, and do not deregulate CDKs. Thus, disruption of a p27 function other than CDK inhibition may contribute to the disease state. A yeast two-hybrid screen identified growth factor receptor-bound protein 2 (GRB2) as a p27 binding partner. We now demonstrate that p27 can inhibit GRB2 function by blocking its association with the guanine nucleotide exchange factor SOS. Endogenous p27 is rapidly exported from the nucleus to the cytoplasm in response to mitogen stimulation, where it binds GRB2 concomitant with a decrease in GRB2-associated SOS. As predicted, mitogen-stimulated p27−/− cells maintained their GRB2-SOS complexes for significantly longer. The Ras/mitogen-activated protein kinase pathway does not appear to be deregulated in cells lacking p27 despite excess GRB2-SOS, suggesting that additional control mechanisms are present. A transient-transfection approach was employed to show that p27 can inhibit Ras activation by targeting GRB2 and further revealed that the CDK and GRB2 inhibitory functions of p27 are separable and distinct. Thus, p27 downregulation may compromise control of Ras, one of the most common oncogenic events in human cancer.

scholarly journals Cleavage of the signaling mucin Msb2 by the aspartyl protease Yps1 is required for MAPK activation in yeast

2008 ◽  
Vol 181 (7) ◽  
pp. 1073-1081 ◽  
Author(s):  
Nadia Vadaie ◽  
Heather Dionne ◽  
Darowan S. Akajagbor ◽  
Seth R. Nickerson ◽  
Damian J. Krysan ◽  
...  
Keyword(s):  
Mapk Pathway ◽  
Active Form ◽  
Cell Polarization ◽  
Mitogen Activated Protein Kinase ◽  
Aspartyl Protease ◽  
Nucleotide Exchange ◽  
Mapk Activation ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factor ◽  
Mitogen Activated Protein

Signaling mucins are cell adhesion molecules that activate RAS/RHO guanosine triphosphatases and their effector mitogen-activated protein kinase (MAPK) pathways. We found that the Saccharomyces cerevisiae mucin Msb2p, which functions at the head of the Cdc42p-dependent MAPK pathway that controls filamentous growth, is processed into secreted and cell-associated forms. Cleavage of the extracellular inhibitory domain of Msb2p by the aspartyl protease Yps1p generated the active form of the protein by a mechanism incorporating cellular nutritional status. Activated Msb2p functioned through the tetraspan protein Sho1p to induce MAPK activation as well as cell polarization, which involved the Cdc42p guanine nucleotide exchange factor Cdc24p. We postulate that cleavage-dependent activation is a general feature of signaling mucins, which brings to light a novel regulatory aspect of this class of signaling adhesion molecule.

scholarly journals Ras Is Required for the Cyclic AMP-Dependent Activation of Rap1 via Epac2

2008 ◽  
Vol 28 (23) ◽  
pp. 7109-7125 ◽  
Author(s):  
Chang Liu ◽  
Maho Takahashi ◽  
Yanping Li ◽  
Shuang Song ◽  
Tara J. Dillon ◽  
...  
Keyword(s):  
Cyclic Amp ◽  
Sympathetic Neurons ◽  
Nucleotide Exchange ◽  
Cellular Functions ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factor ◽  
Ras Activation ◽  
Mitogen Activated Protein ◽  
Bona Fide ◽  
First Time

ABSTRACT Exchange proteins activated by cAMP (cyclic AMP) 2 (Epac2) is a guanine nucleotide exchange factor for Rap1, a small G protein involved in many cellular functions, including cell adhesion, differentiation, and exocytosis. Epac2 interacts with Ras-GTP via a Ras association (RA) domain. Previous studies have suggested that the RA domain was dispensable for Epac2 function. Here we show for the first time that Ras and cAMP regulate Epac2 function in a parallel fashion and the Ras-Epac2 interaction is required for the cAMP-dependent activation of endogenous Rap1 by Epac2. The mechanism for this requirement is not allosteric activation of Epac2 by Ras but the compartmentalization of Epac2 on the Ras-containing membranes. A computational modeling is consistent with this compartmentalization being a function of both the level of Ras activation and the affinity between Ras and Epac2. In PC12 cells, a well-established model for sympathetic neurons, the Epac2 signaling is coupled to activation of mitogen-activated protein kinases and contributes to neurite outgrowth. Taken together, the evidence shows that Epac2 is not only a cAMP sensor but also a bona fide Ras effector. Coincident detection of both cAMP and Ras signals is essential for Epac2 to activate Rap1 in a temporally and spatially controlled manner.

scholarly journals Two Ras Pathways in Fission Yeast Are Differentially Regulated by Two Ras Guanine Nucleotide Exchange Factors

2002 ◽  
Vol 22 (13) ◽  
pp. 4598-4606 ◽  
Author(s):  
Piyi Papadaki ◽  
Véronique Pizon ◽  
Brian Onken ◽  
Eric C. Chang
Keyword(s):  
Mitogen Activated Protein Kinase ◽  
Critical Element ◽  
Guanine Nucleotide ◽  
Nucleotide Exchange ◽  
Signaling Specificity ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factor ◽  
Mitogen Activated Protein ◽  
Kinase Cascade ◽  
Synthetically Lethal

ABSTRACT How a given Ras prreotein coordinates multiple signaling inputs and outputs is a fundamental issue of signaling specificity. Schizosaccharomyces pombe contains one Ras, Ras1, that has two distinct outputs. Ras1 activates Scd1, a presumptive guanine nucleotide exchange factor (GEF) for Cdc42, to control morphogenesis and chromosome segregation, and Byr2, a component of a mitogen-activated protein kinase cascade, to control mating. So far there is only one established Ras1 GEF, Ste6. Paradoxically, ste6 null (ste6Δ) mutants are sterile but normal in cell morphology. This suggests that Ste6 specifically activates the Ras1-Byr2 pathway and that there is another GEF capable of activating the Scd1 pathway. We thereby characterized a potential GEF, Efc25. Genetic data place Efc25 upstream of the Ras1-Scd1, but not the Ras1-Byr2, pathway. Like ras1Δ and scd1Δ, efc25Δ is synthetically lethal with a deletion in tea1, a critical element for cell polarity control. Using truncated proteins, we showed that the C-terminal GEF domain of Efc25 is essential for function and regulated by the N terminus. We conclude that Efc25 acts as a Ras1 GEF specific for the Scd1 pathway. While ste6 expression is induced during mating, efc25 expression is constitutive. Moreover, Efc25 overexpression renders cells hyperelongated and sterile; the latter can be rescued by activated Ras1. This suggests that Efc25 can recruit Ras1 to selectively activate Scd1 at the expense of Byr2. Reciprocally, Ste6 overexpression can block Scd1 activation. We propose that external signals can partly segregate two Ras1 pathways by modulating GEF expression and that GEFs can influence how Ras is coupled to specific effectors.

scholarly journals Ras isoforms: signaling specificities in CD40 pathway

2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Arathi Nair ◽  
Sushmita Chakraborty ◽  
Late Anirban Banerji ◽  
Ankita Srivastava ◽  
Charudutta Navare ◽  
...  
Keyword(s):  
Leishmania Major ◽  
Phosphatidyl Inositol ◽  
Mitogen Activated Protein Kinase ◽  
High Dose ◽  
Nucleotide Exchange ◽  
Ras Activation ◽  
Mitogen Activated Protein ◽  
Cd40 Stimulation ◽  
Ras Isoforms ◽  
Deficient Mice

Abstract Background Ras are small cellular GTPases which regulate diverse cellular processes. It has three isoforms: H-Ras, K-Ras, and N-Ras. Owing to the N-terminus (1–165 residues) sequence homology these isoforms were thought to be functionally redundant. However, only K-Ras-deficient mice but not H-Ras- and N-Ras-deficient mice show embryonic lethality. Similarly, mutations in a given Ras isoform are associated with a particular type of cancer. Moreover, we have previously reported that Ras isoforms perform unique functions in Leishmania major infection. Thus, Ras isoforms are implicated to have signaling and functional specificity but the mechanism remains to be elucidated. Result Using CD40 as a model receptor, we showed that depending on the strength of signaling, specific Ras isoforms are activated. Weak CD40 signal activates N-Ras, whereas strong signal activates H-Ras and K-Ras. Additionally, we showed that suppression of N-Ras expression reduced CD40-induced extracellular signal–regulated kinase-1/2 (ERK-1/2) activation and Interleukin (IL)-10 production; whereas suppression of H-Ras or K-Ras reduced CD40-induced p38 mitogen-activated protein kinase (p38MAPK) activation and IL-12 production. Furthermore, we showed that Ras isoforms have activator (GEF) specificity as weak CD40 signal-activated N-Ras requires Sos-1/2 whereas strong CD40 signal-activated H-Ras/K-Ras requires Ras-GRP as the guanine-nucleotide exchange factor (GEF) inducing ERK-1/2- or p38MAPK-mediated IL-10 or IL-12 productions, respectively, in macrophages. Silencing of syk reduced CD40-induced N-Ras activation but silencing of lyn inhibited H-Ras and K-Ras activation. In CD40 signaling, Ras isoforms also showed effector specificity; while H-Ras and K-Ras showed specificity for phosphatidyl inositol-3 kinase activation at high dose of CD40 stimulation, N-Ras primarily associated with Raf-1 at low dose of CD40 stimulation. Moreover, fractal analysis showed that functional site surface roughness for H-Ras (SurfaceFD = 2.39) and K-Ras (SurfaceFD = 2.39) are similar but significantly different from N-Ras (SurfaceFD = 2.25). Conclusion The activator and effector specificities of Ras isoforms in CD40 signaling indicated their differential involvement in CD40 pathway and in maintaining the reciprocity. Our observations reveal Ras-regulated signaling outcome and its potential for developing Ras isoform-targeted immunotherapy and prophylaxis. Graphical abstract

scholarly journals Semaphorin 4D activates the MAPK pathway downstream of plexin-B1

2006 ◽  
Vol 394 (2) ◽  
pp. 459-464 ◽  
Author(s):  
Jennifer Aurandt ◽  
Weiquan Li ◽  
Kun-Liang Guan
Keyword(s):  
Nervous System ◽  
Mapk Pathway ◽  
Large Family ◽  
Cellular Systems ◽  
Mitogen Activated Protein Kinase ◽  
Nucleotide Exchange ◽  
Semaphorin 4D ◽  
C Terminus ◽  
Nucleotide Exchange Factor ◽  
Mitogen Activated Protein

Semaphorins are a large family of transmembrane and secreted proteins that signal primarily through the receptor plexin. Semaphorins have been characterized in the nervous system as axon guidance cues; however, they have also been shown to control development of other cellular systems such as the vasculature and lungs. As the role of semaphorins outside of the nervous system has broadened, so has elucidation of the intracellular signalling pathways they initiate. Previously, we and others have shown that plexin-B1 activates RhoA through the binding and activation of RhoGEF (guanine nucleotide-exchange factor)/LARG (leukaemia-associated RhoGEF) in response to semaphorin 4D stimulation. In the present study, we show that semaphorin 4D activates the MAPK (mitogen-activated protein kinase) pathway. We have found that the mechanism of activation requires the C-terminus of plexin-B1 and the activation of RhoA.

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