Currie RA, Walker KS, Gray A, Deak M, Casamayor A, Downes CP, Cohen P, Alessi DR, Lucocq J: Role of phosphatidylinositol 3,4,5-trisphosphate in regulating the activity and localization of 3-phosphoinositide-dependent protein kinase-1. 2001, 276: 14414-14419. Surprisingly, only one phosphorylation site requires the catalytic activity of Src, whereas phosphorylation on four other sites requires the intact SH2 domain of Src but not its catalytic activity [111]. Indeed, a comprehensive study done by Knight and colleagues revealed specific functions of class PI3Ks in insulin signalling [157]. 2002, 13: 1550-1565. 2002, 14: 140-148. J Mol Cell Cardiol. Neuron. 2009, 297: C1434-1444. 1994, 14: 7527-7534. In addition, kinase independent and dependent ERK functions may collaborate to form autoregulatory feedback loops. Kholodenko BN: Cell-signalling dynamics in time and space. Shishido T, Woo CH, Ding B, McClain C, Molina CA, Yan C, Yang J, Abe J: Effects of MEK5/ERK5 association on small ubiquitin-related modification of ERK5: implications for diabetic ventricular dysfunction after myocardial infarction. miRNA-125b expressed in skeletal muscle cells negatively regulates muscle differentiation and injury-induced muscle regeneration by downregulating IGF-II, which is required for this process. 2011, 407: 248-253. Thus, MKP3 may not only function as inhibitor, but rather shape spatiotemporal gradients of ERK activation. Krebs EG, Fischer EH: The phosphorylase b to a converting enzyme of rabbit skeletal muscle. There, the EGFR associates with Sec61, and is subsequently retrotranslocated from the ER to the cytoplasm. PLoS ONE. 2010, 3: 705-720. This activity required the conformational change of PAK, since activated Rac or Cdc42 were able to promote this effect [135]. Mamm Genome. These results suggest important kinase independent functions of Src in integrin signalling and cytoskeletal organization. 2008, 13: 385-393.

1996, 383: 181-185. 2006, 26: 2262-2272. Genes Dev. 2009, 29: 5193-5202. The increase in nuclear ERK caused by ERK activation eventually can dislodge C/EBP- from the promoter again and terminate transcription. Farrar MA, Alberol I, Perlmutter RM: Activation of the Raf-1 kinase cascade by coumermycin-induced dimerization. 2007, 6: 2429-2433. In another example from budding yeast, Madhani and colleagues showed in 1997 that the MAPK Kss1 has important non-catalytic functions [7]. The mechanism may include heterodimerization with other ERBB members. There are only few examples, but as ERK tends to associate with its substrates in rather stable pre-activation complexes [36] this type of regulation may be more widespread than currently appreciated. Mao K, Kobayashi S, Jaffer ZM, Huang Y, Volden P, Chernoff J, Liang Q: Regulation of Akt/PKB activity by P21-activated kinase in cardiomyocytes. The KSR2 targeted phosphorylation sites in MEK were different from the known regulatory sites suggesting that the combination of a scaffold with the allosteric activation of a pseudokinase domain may confer exquisite substrate specificity. 2010, 363: 809-819. In eukaryotes, the protein kinase family is one of the largest gene families, counting for about 2% of all genes. Anyone you share the following link with will be able to read this content: Sorry, a shareable link is not currently available for this article. ASK1inhibits NFB activation by interfering with the formation of the TRAF6/TAK1 complex that mediates interleukin-1 induced TAK1 activation [80]. Molecular and cellular biology. 2010, 11: 1085-1092. Since PIP3 is required for -adrenergic receptor internalization, PKA helps to maintain receptor levels on the plasma membrane. Indeed, FAK knockdown induced p53 activation and cell cycle arrest in endothelial cells, but a subsequent increase in Pyk2 expression led to p53 downregulation and the release of cell cycle block [128]. Gnesutta N, Minden A: Death receptor-induced activation of initiator caspase 8 is antagonized by serine/threonine kinase PAK4. Cancer Res. Biochim Biophys Acta. 2005, 174: 1385-1392. Chromatin immunoprecipitation (ChIP) experiments indicated that mTOR binds to the dystrophin promoter [195]. 1991, 88: 8277-8281. MAPK pathways are ubiquitous signaling modules consisting of a three-tiered, and sometimes four-tiered, cascade of kinases that is activated by a small G-protein as input (Figure 3A). Rodrguez J, Calvo F, Gonzlez JM, Casar B, Andrs V, Crespo P: ERK1/2 MAP kinases promote cell cycle entry by rapid, kinase-independent disruption of retinoblastoma-lamin A complexes. Ras contributes to Ral activation by bringing the Ral-GDS proximate to its substrate, but is not sufficient for the full catalytic activation of Ral-GDS [186]. Krebs EG, Kent AB, Fischer EH: The muscle phosphorylase b kinase reaction. Curr Biol. Thus, similar as FAK, Pyk2 promotes Mdm2-dependent p53 ubiquitination to facilitate cell proliferation and survival in a kinase-independent manner (Figure 5B). Usually, the catalytic activity of PARP-1 is stimulated by DNA strand breaks, and its activation is required for initiation of DNA repair. 2010, 102: 1-15. In addition, PKA phosphorylates p110 and inhibits its kinase activity, thus decreasing the PIP3 levels. (A) PDK1 induces activation of the Ral small G protein by binding to and relieving its GEF, Ral-GDS from the autoinhibitory conformation. In addition to that, the expression level of the regulatory subunit p101 is elevated as well. 1995, 9: 1505-1517. Fernandez N, Gottardo FL, Alonso MN, Monczor F, Shayo C, Davio C: Roles of phosphorylation dependent and independent mechanisms in the regulation of Histamine H2 receptor by G Protein-coupled Receptor Kinase 2. Oppermann FS, Gnad F, Olsen JV, Hornberger R, Greff Z, Keri G, Mann M, Daub H: Large-scale proteomics analysis of the human kinome. Molli PR, Li DQ, Murray BW, Rayala SK, Kumar R: PAK signaling in oncogenesis. The Journal of biological chemistry. The assembly of this complex does not require PI3K catalytic activity, although kinase competent PI3K is more efficient [161].

J Cell Biol. Cell. Qu J, Li X, Novitch BG, Zheng Y, Kohn M, Xie JM, Kozinn S, Bronson R, Beg AA, Minden A: PAK4 kinase is essential for embryonic viability and for proper neuronal development. Besides their canonical kinase dependent functions, both ERK kinases were shown to influence their substrates not only by phosphorylation, but also by direct protein-protein interactions independently of ERK kinase activity [8183]. Mitsushima M, Toyoshima F, Nishida E: Dual role of Cdc42 in spindle orientation control of adherent cells. Holbro T, Beerli RR, Maurer F, Koziczak M, Barbas CF, Hynes NE: The ErbB2/ErbB3 heterodimer functions as an oncogenic unit: ErbB2 requires ErbB3 to drive breast tumor cell proliferation. The activation of the first kinase, MAPKKK, is initiated by it binding to an activated Ras or Rho family protein. 2009, 284: 8023-8032.

Proceedings of the National Academy of Sciences of the United States of America. Recent structural and molecular dynamics based modelling studies showed that the ErbB3 pseudokinase domain uses an alternative phosphotransfer mechanism to transautophosphorylate its intracellular region [203]. Science (New York, NY). This observation suggests that during evolution the role of Raf might have shifted from activating the ERK pathway to inhibiting the MST2 pathway. J Cell Biol. 2006, 16: 1337-1343. 1993, 74: 633-643. 2002, 1: 703-708. Embo J. 2004, 167: 469-478. 2007, 18: 1064-1072. Jorgensen R, Holliday ND, Hansen JL, Vrecl M, Heding A, Schwartz TW, Elling CE: Characterization of G-protein coupled receptor kinase interaction with the neurokinin-1 receptor using bioluminescence resonance energy transfer. RTKs are starting points for several signalling pathways, and hence are not only key regulators of many normal cellular processes, but also play a major role in development and progression of many malignancies [9]. ERBB2's kinase activity, but not tyrosine phosphorylation, was required for this activation. 2010, 107: 7692-7697. Expression of the N-terminal regulatory domain of PAK1, which seems to interfere with the ability of PAK to recruit PDK1, preferentially reduced the phosphorylation of nuclear Akt substrates, such as FoxO3a, while the phosphorylation levels of the cytosolic substrates S6K, BAD and GSK3 remained intact. Most kinases mentioned in this review were first identified as enzymes, and only later additional functional functions were identified. (B) FAK and the related kinase Pyk2 can translocate to the nucleus where they bind p53 and Mdm2 to induce p53 ubiquitination and degradation, promoting cell proliferation and survival. 2009, 107: 65-75. Camps M: Catalytic Activation of the Phosphatase MKP-3 by ERK2 Mitogen-Activated Protein Kinase. Besides Raf kinases and PI3K, Ral-GDS is one of the three classic Ras effectors [184, 185]. From a therapeutic point of view, targeting these catalytic-independent Raf interactions (ROK-alpha, ASK1, MST2) in cancer might prove to be a good strategy. Another potential target of kinase-independent ASK1-induced apoptosis is the transcription factor nuclear factor-kappaB (NFB), a key regulator of immune and inflammatory responses that exerts anti-apoptotic roles in various cells. Campos-Gonzalez R, Glenney JR: Tyrosine phosphorylation of mitogen-activated protein kinase in cells with tyrosine kinase-negative epidermal growth factor receptors. Proceedings of the National Academy of Sciences of the United States of America. EGFR and other ERBB receptors are known to be regulated by endocytosis. 2010, 107: 7491-7496. The kinase domain of PAK1 directly interacts with Akt and mediates its translocation to the plasma membrane, where S473 can be phosphorylated by mTORC2 [143] or PAK itself [141, 142]. 2006, 22: 489-499. EGFR forms homodimers as well as three functional heterodimers with the other members of the ERBB family, which stimulates its intrinsic intracellular protein-tyrosine kinase activity and results in autophosphorylation of several tyrosine residues in the C-terminal domain of EGFR [13]. Similar to Raf-1, A-Raf kinase activity is not required as kinase-dead A-Raf mutants also can inhibit MST2 activation. This can be explained by an ability of PI3K to form a complex with phosphodiesterase 3B (PDE3B) independently of its kinase activity. Science. The Journal of Cell Biology. The reason for this discrepancy is unclear. Cellular signalling. This cascade is a main effector pathway of ERBB receptors, and altered in a high percentage of cancers usually be mutation of Ras or BRAFgenes.