Reactome: A Curated Pathway Database
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RHO GTPases activate PKNs

Stable Identifier
R-HSA-5625740
Type
Pathway
Species
Homo sapiens
Locations in the PathwayBrowser
Summation

Protein kinases N (PKN), also known as protein kinase C-related kinases (PKR) feature a C-terminal serine/threonine kinase domain and three RHO-binding motifs at the N-terminus. RHO GTPases RHOA, RHOB, RHOC and RAC1 bind PKN1, PKN2 and PKN3 (Maesaki et al. 1999, Zhong et al. 1999, Owen et al. 2003, Modha et al. 2008, Hutchinson et al. 2011, Hutchinson et al. 2013), bringing them in proximity to the PIP3-activated co-activator PDPK1 (PDK1) (Flynn et al. 2000, Torbett et al. 2003). PDPK1 phosphorylates PKNs on a highly conserved threonine residue in the kinase activation loop, which is a prerequisite for PKN activation. Phosphorylation of other residues might also be involved in activation (Flynn et al. 2000, Torbett et al. 2003, Dettori et al. 2009). PKNs are activated by fatty acids like arachidonic acid and phospholipids in vitro, but the in vivo significance of this activation remains unclear (Palmer et al. 1995, Yoshinaga et al. 1999).

PKNs play important roles in diverse functions, including regulation of cell cycle, receptor trafficking, vesicle transport and apoptosis. PKN is also involved in the ligand-dependent transcriptional activation by the androgen receptor. More than 20 proteins and several peptides have been shown to be phosphorylated by PKN1 and PKN2, including CPI-17 (Hamaguchi et al. 2000), alpha-actinin (Mukai et al. 1997), adducin (Collazos et al. 2011), CDC25C (Misaki et al. 2001), vimentin (Matsuzawa et al. 1997), TRAF1 (Kato et al. 2008), CLIP170 (Collazos et al. 2011) and EGFR (Collazos et al. 2011). There are no known substrates for PKN3 (Collazos et al. 2011).

Literature References
PubMed ID Title Journal Year
10619026 The structural basis of Rho effector recognition revealed by the crystal structure of human RhoA complexed with the effector domain of PKN/PRK1 Mol. Cell 1999
21351730 Mutational analysis reveals a single binding interface between RhoA and its effector, PRK1 Biochemistry 2011
9175763 Domain-specific phosphorylation of vimentin and glial fibrillary acidic protein by PKN Biochem. Biophys. Res. Commun. 1997
11134534 PKN delays mitotic timing by inhibition of Cdc25C: possible involvement of PKN in the regulation of cell division Proc. Natl. Acad. Sci. U.S.A. 2001
9030526 Interaction of PKN with alpha-actinin J. Biol. Chem. 1997
18429822 Negative regulation of constitutive NF-kappaB and JNK signaling by PKN1-mediated phosphorylation of TRAF1 Genes Cells 2008
14514689 Molecular dissection of the interaction between the small G proteins Rac1 and RhoA and protein kinase C-related kinase 1 (PRK1) J. Biol. Chem. 2003
7673228 Activation of PRK1 by phosphatidylinositol 4,5-bisphosphate and phosphatidylinositol 3,4,5-trisphosphate. A comparison with protein kinase C isotypes J. Biol. Chem. 1995
24128008 Differential binding of RhoA, RhoB, and RhoC to protein kinase C-related kinase (PRK) isoforms PRK1, PRK2, and PRK3: PRKs have the highest affinity for RhoB Biochemistry 2013
12783890 Hyperosmotic-induced protein kinase N 1 activation in a vesicular compartment is dependent upon Rac1 and 3-phosphoinositide-dependent kinase 1 J. Biol. Chem. 2003
10753910 Rho GTPase control of protein kinase C-related protein kinase activation by 3-phosphoinositide-dependent protein kinase J. Biol. Chem. 2000
19723632 Regulation of the interaction between protein kinase C-related protein kinase 2 (PRK2) and its upstream kinase, 3-phosphoinositide-dependent protein kinase 1 (PDK1) J. Biol. Chem. 2009
9988689 Loop 6 of RhoA confers specificity for effector binding, stress fiber formation, and cellular transformation J. Biol. Chem. 1999
10467162 Mutational analysis of the regulatory mechanism of PKN: the regulatory region of PKN contains an arachidonic acid-sensitive autoinhibitory domain J. Biochem. 1999
10924361 Phosphorylation of CPI-17, an inhibitor of myosin phosphatase, by protein kinase N Biochem. Biophys. Res. Commun. 2000
21749319 Site recognition and substrate screens for PKN family proteins Biochem. J. 2011
18006505 The Rac1 polybasic region is required for interaction with its effector PRK1 J. Biol. Chem. 2008
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