Pathway maps

G-protein signaling_Ras family GTPases in kinase cascades (scheme)
G-protein signaling_Ras family GTPases in kinase cascades (scheme)

Object List (links open in MetaCore):

MEK2(MAP2K2), PAK1, Elk-1, K-RAS, JNK(MAPK8-10), CDC42, B-Raf, MEK1(MAP2K1), RAP-1A, N-Ras, c-RAF-1, c-Fos, MEKK4(MAP3K4), C/EBPbeta, ERK1/2, Rac1, R-Ras, ATF-2, H-Ras, p38 MAPK, c-Jun, MEK3(MAP2K3), MEKK1(MAP3K1), MEK4(MAP2K4)

Description

Ras family GTPases in kinase cascades

GTPases of the Ras superfamily are activated upon growth factors stimuli and controls a wide range of essential biochemical pathways in all eukaryotic cells. One of the most important functions of Ras proteins is activation of mitogen activated protein kinases (MAPK). MAPK pathways are important intracellular cascades that couple signals from the cell surface to the nucleus. One of the most explored functions of MAPK signaling modules is regulation of gene expression in response to extracellular stimuli. MAPK activity is regulated through three-tiered cascades composed of MAPK, MAPK kinase (MAPKK, MKK or MEK) and MAPKK kinase or MEK kinase (MAPKKK or MEKK) [1]. Members of Ras and Rho subfamilies could activate MAPK cascades by stimulating MEKK kinases.

Main effector of Ras subfamily members v-Ha-ras Harvey rat sarcoma viral oncogene homolog ( H-Ras), v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog ( K-Ras), Neuroblastoma RAS viral (v-ras) oncogene homolog ( N-Ras), and Related RAS viral (r-ras) oncogene homolog ( R-Ras) is v-raf-1 murine leukemia viral oncogene homolog 1 ( c-Raf-1) [2], [3], RAP1A, member of RAS oncogene family ( RAP-1A) is a specific activator of v-raf murine sarcoma viral oncogene homolog B1 ( B-Raf) [4], [5]. Activated Raf proteins phosphorylate Mitogen-activated protein kinase kinases 1 and 2 ( MEK1(MAP2K1) and MEK2(MAP2K2) ), which subsequently phosphorylate Mitogen-activated protein kinases 1 and 3 ( ERK1/2) [1], [3]. ERK1/2 stimulation under Ras signaling leads to activation of a range of transcription factors, such as Jun oncogene ( c-Jun), v-fos FBJ murine osteosarcoma viral oncogene homolog ( c-Fos), ELK1, member of ETS oncogene family ( Elk-1), and CCAAT/enhancer binding protein (C/EBP), beta ( C/EBP beta) [6], [7], [8], [1], [9].

Members of Rho subfamily ras-related C3 botulinum toxin substrate 1 ( Rac1) and Cell division cycle 42 ( CDC42) promotes activation of p21 protein (Cdc42/Rac)-activated kinase 1 ( PAK1), Mitogen-activated protein kinase kinase kinases 1 and 4 ( MEKK1(MAP3K1) and MEKK4(MAP3K4) ), which phosphorylate Mitogen-activated protein kinase kinase 3 and 4 ( MEK3(MAP2K3) and MEK4(MAP2K4) ) and this leads to Mitogen-activated protein kinase 8 -10 ( JNK(MAPK8-10) ) and Mitogen-activated protein kinase 14 ( p38 MAPK) activation [10], [11], [12], [13], [14]. Activated by Rac1 and CDC42 p38 MAPK and JNK(MAPK8-10) could activate their nuclear targets Activating transcription factor 2 ( ATF-2) and c-Jun [15], [16].

In addition, H-RAS signaling can activate MEKK1(MAP3K1), which can promote ERK1/2 activation via c-Raf-1/ MEK1(MAP2K1) or JNK(MAPK8-10) activation via MEK4(MAP2K4) [17], [18], [19], [20].

References:

  1. Chang L, Karin M
    Mammalian MAP kinase signalling cascades. Nature 2001 Mar 1;410(6824):37-40
  2. Reuther GW, Der CJ
    The Ras branch of small GTPases: Ras family members don't fall far from the tree. Current opinion in cell biology 2000 Apr;12(2):157-65
  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. Schmitt JM, Stork PJ
    beta 2-adrenergic receptor activates extracellular signal-regulated kinases (ERKs) via the small G protein rap1 and the serine/threonine kinase B-Raf. The Journal of biological chemistry 2000 Aug 18;275(33):25342-50
  5. Peyssonnaux C, Eych??ne A
    The Raf/MEK/ERK pathway: new concepts of activation. Biology of the cell / under the auspices of the European Cell Biology Organization 2001 Sep;93(1-2):53-62
  6. Karin M
    The regulation of AP-1 activity by mitogen-activated protein kinases. The Journal of biological chemistry 1995 Jul 14;270(28):16483-6
  7. Davis RJ
    The mitogen-activated protein kinase signal transduction pathway. The Journal of biological chemistry 1993 Jul 15;268(20):14553-6
  8. Vossler MR, Yao H, York RD, Pan MG, Rim CS, Stork PJ
    cAMP activates MAP kinase and Elk-1 through a B-Raf- and Rap1-dependent pathway. Cell 1997 Apr 4;89(1):73-82
  9. Guha M, O'Connell MA, Pawlinski R, Hollis A, McGovern P, Yan SF, Stern D, Mackman N
    Lipopolysaccharide activation of the MEK-ERK1/2 pathway in human monocytic cells mediates tissue factor and tumor necrosis factor alpha expression by inducing Elk-1 phosphorylation and Egr-1 expression. Blood 2001 Sep 1;98(5):1429-39
  10. Zhang S, Han J, Sells MA, Chernoff J, Knaus UG, Ulevitch RJ, Bokoch GM
    Rho family GTPases regulate p38 mitogen-activated protein kinase through the downstream mediator Pak1. The Journal of biological chemistry 1995 Oct 13;270(41):23934-6
  11. Fanger GR, Johnson NL, Johnson GL
    MEK kinases are regulated by EGF and selectively interact with Rac/Cdc42. The EMBO journal 1997 Aug 15;16(16):4961-72
  12. Hagemann C, Blank JL
    The ups and downs of MEK kinase interactions. Cellular signalling 2001 Dec;13(12):863-75
  13. Johnson GL, Lapadat R
    Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science (New York, N.Y.) 2002 Dec 6;298(5600):1911-2
  14. Hou Y, Ye RD, Browning DD
    Activation of the small GTPase Rac1 by cGMP-dependent protein kinase. Cellular signalling 2004 Sep;16(9):1061-9
  15. Davis RJ
    Signal transduction by the JNK group of MAP kinases. Cell 2000 Oct 13;103(2):239-52
  16. Saoncella S, Calautti E, Neveu W, Goetinck PF
    Syndecan-4 regulates ATF-2 transcriptional activity in a Rac1-dependent manner. The Journal of biological chemistry 2004 Nov 5;279(45):47172-6
  17. Marshall MS
    Ras target proteins in eukaryotic cells. The FASEB journal : official publication of the Federation of American Societies for Experimental Biology 1995 Oct;9(13):1311-8
  18. Russell M, Lange-Carter CA, Johnson GL
    Direct interaction between Ras and the kinase domain of mitogen-activated protein kinase kinase kinase (MEKK1). The Journal of biological chemistry 1995 May 19;270(20):11757-60
  19. Karandikar M, Xu S, Cobb MH
    MEKK1 binds raf-1 and the ERK2 cascade components. The Journal of biological chemistry 2000 Dec 22;275(51):40120-7
  20. Takahashi H, Honma M, Ishida-Yamamoto A, Namikawa K, Kiyama H, Iizuka H
    Expression of human cystatin A by keratinocytes is positively regulated via the Ras/MEKK1/MKK7/JNK signal transduction pathway but negatively regulated via the Ras/Raf-1/MEK1/ERK pathway. The Journal of biological chemistry 2001 Sep 28;276(39):36632-8