scholarly journals GAREM, a Novel Adaptor Protein for Growth Factor Receptor-bound Protein 2, Contributes to Cellular Transformation through the Activation of Extracellular Signal-regulated Kinase Signaling

2009 ◽  
Vol 284 (30) ◽  
pp. 20206-20214 ◽  
Author(s):  
Kyoko Tashiro ◽  
Takumi Tsunematsu ◽  
Hiroko Okubo ◽  
Takeshi Ohta ◽  
Etsuko Sano ◽  
...  
Keyword(s):  
Growth Factor ◽  
Growth Factor Receptor ◽  
Adaptor Protein ◽  
Cellular Transformation ◽  
Kinase Signaling ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Growth Factor Receptor Bound

scholarly journals Dysfunction of GRAP, encoding the GRB2-related adaptor protein, is linked to sensorineural hearing loss

2019 ◽  
Vol 116 (4) ◽  
pp. 1347-1352 ◽  
Author(s):  
Chong Li ◽  
Guney Bademci ◽  
Asli Subasioglu ◽  
Oscar Diaz-Horta ◽  
Yi Zhu ◽  
...  
Keyword(s):  
Growth Factor ◽  
Growth Factor Receptor ◽  
Adaptor Protein ◽  
Adaptor Proteins ◽  
Ras Signaling ◽  
Nonsyndromic Deafness ◽  
Auditory Hair Cells ◽  
Cytoskeleton Dynamics ◽  
Growth Factor Receptor Bound

We have identified a GRAP variant (c.311A>T; p.Gln104Leu) cosegregating with autosomal recessive nonsyndromic deafness in two unrelated families. GRAP encodes a member of the highly conserved growth factor receptor-bound protein 2 (GRB2)/Sem-5/drk family of proteins, which are involved in Ras signaling; however, the function of the growth factor receptor-bound protein 2 (GRB2)-related adaptor protein (GRAP) in the auditory system is not known. Here, we show that, in mouse, Grap is expressed in the inner ear and the protein localizes to the neuronal fibers innervating cochlear and utricular auditory hair cells. Downstream of receptor kinase (drk), the Drosophila homolog of human GRAP, is expressed in Johnston’s organ (JO), the fly hearing organ, and the loss of drk in JO causes scolopidium abnormalities. drk mutant flies present deficits in negative geotaxis behavior, which can be suppressed by human wild-type but not mutant GRAP. Furthermore, drk specifically colocalizes with synapsin at synapses, suggesting a potential role of such adaptor proteins in regulating actin cytoskeleton dynamics in the nervous system. Our findings establish a causative link between GRAP mutation and nonsyndromic deafness and suggest a function of GRAP/drk in hearing.

scholarly journals Phosphorylation of the Carboxyl-Terminal Transactivation Domain of c-Fos by Extracellular Signal-Regulated Kinase Mediates the Transcriptional Activation of AP-1 and Cellular Transformation Induced by Platelet-Derived Growth Factor

2003 ◽  
Vol 23 (19) ◽  
pp. 7030-7043 ◽  
Author(s):  
Paula Monje ◽  
Maria Julia Marinissen ◽  
J. Silvio Gutkind
Keyword(s):  
Transcription Factors ◽  
Growth Factor ◽  
Cell Growth ◽  
Intracellular Signaling ◽  
Cellular Transformation ◽  
Platelet Derived Growth Factor ◽  
Transactivation Domain ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Carboxyl Terminal

ABSTRACT Polypeptide growth factors, such as platelet-derived growth factor (PDGF), promote the reinitiation of DNA synthesis and cell growth through multiple intracellular signaling pathways that converge in the nucleus to regulate the activity of transcription factors, thereby controlling the expression of growth-promoting genes. Among them, the AP-1 (activating protein-1) family of transcription factors, including c-Fos and c-Jun family members, plays a key role, as AP-1 activity is potently activated by PDGF and is required to stimulate cell proliferation. However, the nature of the pathways connecting PDGF receptors to AP-1 is still poorly defined. In this study, we show that PDGF regulates AP-1 by stimulating the expression and function of c-Fos through extracellular signal-regulated kinase (ERK). The latter involves the direct phosphorylation by ERK of multiple residues in the carboxyl-terminal transactivation domain of c-Fos, which results in its increased transcriptional activity. Interestingly, the phosphorylation of c-Fos by ERK was required for the ability of PDGF and serum to stimulate the activity of c-Fos as well as AP-1-dependent transcription. Furthermore, we provide evidence that the ERK-dependent activation of c-Fos is an integral component of the mitogenic pathway by which PDGF regulates normal and aberrant cell growth.

scholarly journals Crystal structure of the SH3 domain of growth factor receptor-bound protein 2

2020 ◽  
Vol 76 (6) ◽  
pp. 263-270
Author(s):  
Alexandr Bolgov ◽  
Svetlana Korban ◽  
Dmitrii Luzik ◽  
Vladimir Zhemkov ◽  
Meewhi Kim ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Growth Factor ◽  
Cell Communication ◽  
Growth Factor Receptor ◽  
Adaptor Protein ◽  
Full Length ◽  
New Information ◽  
Carboxy Terminal Region ◽  
Carboxy Terminal ◽  
Growth Factor Receptor Bound

This study presents the crystal structure of the N-terminal SH3 (SH3N) domain of growth factor receptor-bound protein 2 (Grb2) at 2.5 Å resolution. Grb2 is a small (215-amino-acid) adaptor protein that is widely expressed and involved in signal transduction/cell communication. The crystal structure of full-length Grb2 has previously been reported (PDB entry 1gri). The structure of the isolated SH3N domain is consistent with the full-length structure. The structure of the isolated SH3N domain was solved at a higher resolution (2.5 Å compared with 3.1 Å for the previously deposited structure) and made it possible to resolve some of the loops that were missing in the full-length structure. In addition, interactions between the carboxy-terminal region of the SH3N domain and the Sos1-binding sites were observed in the structure of the isolated domain. Analysis of these interactions provided new information about the ligand-binding properties of the SH3N domain of Grb2.

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