Pathway Map Details

G-protein signaling_TC21 regulation pathway

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C3G, GRB2, CALDAG-GEFI, RASGRF1, B-Raf, RASA2, DAG, Inositol 1,3,4,5-tetrakisphosphate cytosol, CalDAG-GEFIII, c-Src, Ca('2+) cytosol, c-Raf-1, Neurofibromin, p120GAP, DOK2, DOK1, LCK, TC21, MEK1(MAP2K1), G-protein alpha-12 family, MEK2(MAP2K2), RAP-1A, CalDAG-GEFII, BCR, Erk (MAPK1/3)


TC21 regulation pathway

Related RAS viral (r-ras) oncogene homolog 2 ( TC21 ) belongs to Ras family of small GTPases. It plays pivotal role in cell growth and differentiation [1], [2].

Guanine nucleotide exchange factors (GEFs), which promote GTP loading on TC21 are essential for TC21 activation and GTPase activating proteins (GAPs), which stimulate hydrolysis of GTP to GDP, negatively regulates TC21 activity [3]. Main GEFs for TC21 are RAS guanyl releasing proteins 1, 2 and 3 ( CALDAG-GEFII, CALDAG-GEFI, CALDAG-GEFIII ) that can be activated by increased Ca(2'+) cytosol and DAG levels [2], [4]; Ras protein-specific guanine nucleotide-releasing factor 1 ( RASGRF1 ) that is activated by Lymphocyte-specific protein tyrosine kinase ( Lck ) phosphorylation [5], [2], [6]; and Rap guanine nucleotide exchange factor (GEF) 1 ( C3G ) that is stimulated by Growth factor receptor-bound protein 2 ( GRB2 ) binding [7], [2].

Known GEF for TC21 is RAS p21 protein activator 1 ( p120GAP ) [8], [2]. Breakpoint cluster region ( BCR ) via Docking protein 1 and 2 ( DOK1, DOK2 ) phosphorylation stimulates GAP activity of p120GAP [9], [3]. V-src sarcoma ( c-Src ) phosphorylation and RAP1A, member of RAS oncogene family ( RAP-1A ) binding suppress GAP activity of p120GAP [10], [6]. RAS p21 protein activator 2 ( RASA2 ), activated by Inositol 1,3,4,5-tetrakisphosphate cytosol binding or G-protein alpha-12 family signaling, also exhibits GAP activity towards TC21 [11], [12], [2]. Another known TC21 GAP is Neurofibromin 1 ( Neurofibromin ) [2], [13].

GTP-bound TC21 can stimulate the Raf kinase family members v-raf-1 murine leukemia viral oncogene homolog 1 ( c-Raf-1) and v-raf murine sarcoma viral oncogene homolog B1 (B-raf) and thus promote activation of Mitogen-activated protein kinases 1 and 3 ( Erk(MAPK1/3) ) [14], [15].


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    Activation of the Raf/MAP kinase cascade by the Ras-related protein TC21 is required for the TC21-mediated transformation of NIH 3T3 cells. The EMBO journal 1999 Mar 1;18(5):1270-9
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