Reactome | RHO GTPases activate PKNs

RHO GTPases activate PKNs

Stable Identifier

R-HSA-5625740

Type

Pathway

Species

Homo sapiens

ReviewStatus

5/5

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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
18006505	The Rac1 polybasic region is required for interaction with its effector PRK1 Mott, HR, Campbell, LJ, Owen, D, Nietlispach, D, Buhecha, HR, Modha, R	J. Biol. Chem.	2008
21749319	Site recognition and substrate screens for PKN family proteins Kelly, G, Pang, LC, Mellor, H, Michael, N, Totty, N, Whelan, RD, Parker, PJ, Collazos, A	Biochem. J.	2011
10924361	Phosphorylation of CPI-17, an inhibitor of myosin phosphatase, by protein kinase N Hartshorne, DJ, Kaibuchi, K, Seko, T, Ito, M, Feng, J, Nakano, T, Takase, K, Machida, H, Koyama, M, Hamaguchi, T, Amano, M	Biochem. Biophys. Res. Commun.	2000
10467162	Mutational analysis of the regulatory mechanism of PKN: the regulatory region of PKN contains an arachidonic acid-sensitive autoinhibitory domain Miyamoto, M, Toshimori, M, Mukai, H, Yoshinaga, C, Ono, Y	J. Biochem.	1999
9988689	Loop 6 of RhoA confers specificity for effector binding, stress fiber formation, and cellular transformation Raman, N, Quilliam, LA, Atkinson, SJ, Mickelson-Young, LA, Zong, H	J. Biol. Chem.	1999
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) Engel, M, Dettori, R, Sonzogni, S, Piiper, A, Frödin, M, Neimanis, S, Zeuzem, S, Morrice, NA, Meyer, L, Lopez-Garcia, LA, Biondi, RM	J. Biol. Chem.	2009
10753910	Rho GTPase control of protein kinase C-related protein kinase activation by 3-phosphoinositide-dependent protein kinase Flynn, P, Casamassima, A, Parker, PJ, Mellor, H	J. Biol. Chem.	2000
12783890	Hyperosmotic-induced protein kinase N 1 activation in a vesicular compartment is dependent upon Rac1 and 3-phosphoinositide-dependent kinase 1 Casamassima, A, Parker, PJ, Torbett, NE	J. Biol. Chem.	2003
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 Mott, HR, Owen, D, McLaughlin, SH, Hutchinson, CL, Lowe, PN	Biochemistry	2013
7673228	Activation of PRK1 by phosphatidylinositol 4,5-bisphosphate and phosphatidylinositol 3,4,5-trisphosphate. A comparison with protein kinase C isotypes Dekker, LV, Palmer, RH, Gigg, R, Woscholski, R, Le Good, JA, Parker, PJ	J. Biol. Chem.	1995
14514689	Molecular dissection of the interaction between the small G proteins Rac1 and RhoA and protein kinase C-related kinase 1 (PRK1) Mott, HR, Owen, D, Chirgadze, DY, Nietlispach, D, Brosnan, CE, Parker, PJ, Lowe, PN, Blundell, TL	J. Biol. Chem.	2003
18429822	Negative regulation of constitutive NF-kappaB and JNK signaling by PKN1-mediated phosphorylation of TRAF1 Gotoh, Y, Kato, T, Hoffmann, A, Ono, Y	Genes Cells	2008
9030526	Interaction of PKN with alpha-actinin Shibata, H, Shimakawa, M, Kitagawa, M, Toshimori, M, Mukai, H, Takanaga, H, Miyahara, M, Ono, Y	J. Biol. Chem.	1997
11134534	PKN delays mitotic timing by inhibition of Cdc25C: possible involvement of PKN in the regulation of cell division Misaki, K, Kishimoto, T, Ohsumi, K, Oishi, K, Takahashi, M, Isagawa, T, Mukai, H, Yoshinaga, C, Ono, Y	Proc. Natl. Acad. Sci. U.S.A.	2001
9175763	Domain-specific phosphorylation of vimentin and glial fibrillary acidic protein by PKN Shibata, H, Kaibuchi, K, Matsuzawa, K, Mukai, H, Inagaki, M, Kosako, H, Azuma, I, Matsuura, Y, Amano, M, Ono, Y, Inagaki, N	Biochem. Biophys. Res. Commun.	1997
10619026	The structural basis of Rho effector recognition revealed by the crystal structure of human RhoA complexed with the effector domain of PKN/PRK1 Kaibuchi, K, Kuroda, S, Hakoshima, T, Shimizu, T, Ihara, K, Maesaki, R	Mol. Cell	1999
21351730	Mutational analysis reveals a single binding interface between RhoA and its effector, PRK1 Mott, HR, Owen, D, McLaughlin, SH, Hutchinson, CL, Lowe, PN	Biochemistry	2011