Disease relevance of Gap1

• To begin a genetic analysis of the role of p120 Ras-GAP we identified a homolog from the fruit fly Drosophila melanogaster through its ability to complement the sterility of a Schizosaccharomyces pombe (fission yeast) gap1 mutant strain [1].

High impact information on Gap1

• Inactivation of the locus, Gap1, mimics constitutive activation of the Sevenless receptor tyrosine kinase and eliminates the need for a functional Sevenless protein in the R7 cell [2].
• The tumour-suppressor gene Neurofibromatosis 1 (Nf1) encodes a Ras-specific GTPase activating protein (Ras-GAP) [3].
• In contrast, mutation of Y918, a site capable of binding mammalian rasGAP and PLC-gammal, increases Tor signaling [4].
• Using this technique, we have identified a new mutant, mip (more inner photoreceptors), in which this map shows a striking hyperinnervation [5].
• Cross GTPase-activating protein (CrossGAP)/Vilse links the Roundabout receptor to Rac to regulate midline repulsion [6].

Biological context of Gap1

• Two identified interacting genes were the proto-oncogene Ras1 and its functional antagonist Gap1, prominent intermediaries in known signal transduction pathways [7].
• The Gap1 catalytic domain alone is not sufficient for in vivo activity, indicating a requirement for the additional domains [8].
• Furthermore, we find a strong positive genetic interaction between Gap1 and phospholipase Cgamma (PLCgamma), an enzyme which generates inositol-1,4,5-trisphosphate, a precursor for IP4 and a second messenger for intracellular Ca2+ release [8].
• The amino acid sequence shows a high degree of similarity to the entire sequence of the Drosophila melanogaster Gap1 gene [9].
• Widespread Egf-r mRNA down-regulation can be induced by ubiquitous expression of rhomboid or by eliminating the Gap1 gene [10].

Anatomical context of Gap1

• Coimmunoprecipitation experiments in COS cells confirmed that HsAIRK-1 and HsAIRK-2 both interact with RasGAP [11].
• RasGAP pull-down experiments showed that it interacts with HsAIRK-1 in G(2)/M HeLa cells [11].

Associations of Gap1 with chemical compounds

• An inositol-1,3,4, 5-tetrakisphosphate (IP4)-sensitive extended PH domain is essential for Gap1 activity, while Ca2+-sensitive C2 domains and a glutamine-rich region contribute equally to full activity in vivo [8].
• These results show that RasGAP can function as an inhibitor of signaling pathways mediated by Ras and receptor tyrosine kinases in vivo [1].
• The interaction is dependent on the SH2 (Src homology 2) domains of RasGAP, which have been shown to interact with a phosphotyrosine residue within the consensus sequence (phospho)YXXPXD [12].
• Identification of Aurora kinases as RasGAP Src homology 3 domain-binding proteins [11].

Other interactions of Gap1

• Ras1+ is a positive modifier of pb activity both in normal and ectopic cell contexts, while the Ras1-antagonist Gap1 has an opposite effect [7].
• Since receptor tyrosine kinases (RTKs) trigger an increase in intracellular Ca2+ and IP4 concentration through stimulation of PLCgamma, RTKs may stimulate not only activation of Ras but also its deactivation by Gap1, thereby moderating the strength and duration of the Ras signal [8].
• Further, lethal insertions in replication factor complex 4 (rfc4) and GTPase-activating protein 1 (Gap1) exhibit specific mitotic chromosome defects, discovering previously unknown roles for these proteins in chromosome inheritance [13].
• p120 Ras GTPase-activating protein associates with fibroblast growth factor receptors in Drosophila [12].
• Dynamic expression of d-CdGAPr, a novel Drosophila melanogaster gene encoding a GTPase activating protein [14].

Analytical, diagnostic and therapeutic context of Gap1

• Sequence analysis revealed that the 2842-bp cDNA encodes a putative 628-amino acid protein product, which is a member of the GTPase-activating protein (GAP) family [15].

References