G-protein signaling - TC21 regulation pathway

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 [2], [5], [6]; and Rap guanine nucleotide exchange factor (GEF) 1 (C3G) that is stimulated by Growth factor receptor-bound protein 2 (GRB2) binding [2], [7].

Known GEF for TC21 is RAS p21 protein activator 1 (p120GAP) [2], [8]. Breakpoint cluster region (BCR) via Docking protein 1 and 2 (DOK1, DOK2) phosphorylation stimulates GAP activity of p120GAP [3], [9]. V-src sarcoma (c-Src) phosphorylation and RAP1A, member of RAS oncogene family (RAP-1A) binding suppress GAP activity of p120GAP [6], [10]. 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 [2], [11], [12]. 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].

References:

1. Movilla N, Crespo P, Bustelo XR
   Signal transduction elements of TC21, an oncogenic member of the R-Ras subfamily of GTP-binding proteins. Oncogene 1999 Oct 21;18(43):5860-9
2. Ohba Y, Mochizuki N, Yamashita S, Chan AM, Schrader JW, Hattori S, Nagashima K, Matsuda M
   Regulatory proteins of R-Ras, TC21/R-Ras2, and M-Ras/R-Ras3. The Journal of biological chemistry 2000 Jun 30;275(26):20020-6
3. Ehrhardt A, Ehrhardt GR, Guo X, Schrader JW
   Ras and relatives--job sharing and networking keep an old family together. Experimental hematology 2002 Oct;30(10):1089-106
4. Cullen PJ, Lockyer PJ
   Integration of calcium and Ras signalling. Nature reviews. Molecular cell biology 2002 May;3(5):339-48
5. Overbeck AF, Brtva TR, Cox AD, Graham SM, Huff SY, Khosravi-Far R, Quilliam LA, Solski PA, Der CJ
   Guanine nucleotide exchange factors: activators of Ras superfamily proteins. Molecular reproduction and development 1995 Dec;42(4):468-76
6. Giglione C, Gonfloni S, Parmeggiani A
   Differential actions of p60c-Src and Lck kinases on the Ras regulators p120-GAP and GDP/GTP exchange factor CDC25Mm. European journal of biochemistry / FEBS 2001 Jun;268(11):3275-83
7. Smit L, van der Horst G, Borst J
   Sos, Vav, and C3G participate in B cell receptor-induced signaling pathways and differentially associate with Shc-Grb2, Crk, and Crk-L adaptors. The Journal of biological chemistry 1996 Apr 12;271(15):8564-9
8. Graham SM, Vojtek AB, Huff SY, Cox AD, Clark GJ, Cooper JA, Der CJ
   TC21 causes transformation by Raf-independent signaling pathways. Molecular and cellular biology 1996 Nov;16(11):6132-40
9. Carpino N, Wisniewski D, Strife A, Marshak D, Kobayashi R, Stillman B, Clarkson B
   p62(dok): a constitutively tyrosine-phosphorylated, GAP-associated protein in chronic myelogenous leukemia progenitor cells. Cell 1997 Jan 24;88(2):197-204
10. Hata Y, Kikuchi A, Sasaki T, Schaber MD, Gibbs JB, Takai Y
    Inhibition of the ras p21 GTPase-activating protein-stimulated GTPase activity of c-Ha-ras p21 by smg p21 having the same putative effector domain as ras p21s. The Journal of biological chemistry 1990 May 5;265(13):7104-7
11. Lockyer PJ, Bottomley JR, Reynolds JS, McNulty TJ, Venkateswarlu K, Potter BV, Dempsey CE, Cullen PJ
    Distinct subcellular localisations of the putative inositol 1,3,4,5-tetrakisphosphate receptors GAP1IP4BP and GAP1m result from the GAP1IP4BP PH domain directing plasma membrane targeting. Current biology : CB 1997 Dec 1;7(12):1007-10
12. Jiang Y, Ma W, Wan Y, Kozasa T, Hattori S, Huang XY
    The G protein G alpha12 stimulates Bruton's tyrosine kinase and a rasGAP through a conserved PH/BM domain. Nature 1998 Oct 22;395(6704):808-13
13. Huang Y, Rangwala F, Fulkerson PC, Ling B, Reed E, Cox AD, Kamholz J, Ratner N
    Role of TC21/R-Ras2 in enhanced migration of neurofibromin-deficient Schwann cells. Oncogene 2004 Jan 15;23(2):368-78
14. Rosario M, Paterson HF, Marshall CJ
    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
15. Kolch W
    Meaningful relationships: the regulation of the Ras/Raf/MEK/ERK pathway by protein interactions. The Biochemical journal 2000 Oct 15;351 Pt 2:289-305