p21 activated kinases

from Wikipedia, the free encyclopedia

p21-activated kinases ( PAK ) are a family of enzymes that belong to the serine / threonine protein kinases . These kinases are activated by the protein CDK inhibitor 1 (p21). The activity of PAK1, PAK2 and PAK3 is stimulated by binding to the Rho-GTPases Rac and CDC42 , while PAK4, PAK5 and PAK6 act independently of Rho-GTPases. PAHs play an important role in numerous cellular processes, e.g. B. in signal transduction , organization of the cytoskeleton , cellular morphogenesis , gene transcription and the survival of the cell.

properties

Structure and activation

Specific to the Group I PAH which is autoinhibitory domain (Engl. Autoinhibitory domain , AID), which with the GTPase overlaps binding domain (GBD) and therefore an important role for PAK activation plays. Binding to CDC42 or Rac initiates autophosphorylation, which leads to activation of the kinases. The inhibition occurs through dimerization, in which the AID binds to the protein kinase domain.

Group II, on the other hand, has domains similar to AID. It contains an autoinhibitory pseudosubstrate (English. Autoinhibitory pseudosubstrate , PS), such as. B. the AID, and is next to the GBD. The PS is a proline-rich region and is able to interact with proteins that contain an SH3 domain . Autoinhibitory pseudosubstrates are recognized by the protein kinase domain, which leads to interaction between the domains and to inhibition. By binding to an SH3 domain, the interaction is interrupted by autophosphorylation and leads to activation.

Organization of the cytoskeleton

The effectors CDC42 and Rac are known to be regulatory proteins of the cytoskeleton . PAHs mainly regulate the cytoskeleton with the help of polymerized actin structures through the formation of filopodia and lamellipodia ; they also participate in the organization of microtubules .

Myosins also play an important role in the organization of the cytoskeleton. Group I phosphorylates a serine residue of the myosin light chain (MLC) in nerve cells . This stabilizes the polymerized actin and can regulate the formation of thorn processes . They also phosphorylate the light chain of myosin IV, which is involved in membrane transport and cell migration.

Another substrate for both groups is LIM kinase 1 (LIMK1). When the protein is phosphorylated, the protein cofilin is also phosphorylated, which inhibits the depolymerization of actin in order to stabilize the actin filaments. Filamin A is another regulatory protein. It belongs to the actin-binding proteins (ABP) and connects actin filaments with the cell membrane. Filamin A is phosphorylated by PAK1 in order to ensure control of actin stability. Filamin A can also bind to the GBD of PAK1 in order to stimulate its kinase activity. The Arp 2/3 complex also takes part in the organization of the cytoskeleton. He controls the actin nucleation and the branching of the actin filaments. Phosphorylation of subunit 1B of the Arp 2/3 complex (p41) stimulates the arrangement of the complex in the cell cortex of migrating cells and is therefore important for cell motility .

PAH in cancer

PAHs are also considered to be the cause of various oncogenic signal transductions. Furthermore, it has been proven that PAHs promote cell proliferation, regulate apoptosis and accelerate mitotic abnormalities, so that it leads to tumor formation and cell invasiveness. Alterations in PAK expression have been discovered in human tumors. Thus, new therapeutic methods are to be developed in the future.

Subfamilies

The human PAK family contains six serine / threonine protein kinases, which can be divided into two subfamilies based on the structure of the various protein domains and the regulation:

Group I (Group A) function
PAK1 intercellular signal transport processes of integrins and receptor kinases , cell migration , cell adhesion , proliferation , apoptosis , mitosis , gene transcription , control of the cell cycle, vesicle transport processes
PAK2 Signal transduction, regulation of the cytoskeleton and cell motility , control of the cell cycle, apoptosis and cell proliferation
PAK3 Signal transduction, cell migration, regulation of the cytoskeleton and the cell cycle
Group II (Group B) function
PAK4 Signal transduction, regulation of the cytoskeleton, cell migration, cell growth , cell proliferation, cell survival
PAK5 Regulation of the cytoskeleton, cell migration, cell proliferation, cell survival
PAK6 Gene transcription, regulation of the cytoskeleton

Inhibition

The p21-activated kinases can also act as inhibitors . Thereby phosphorylate the PAK-specific proteins, so that the regulation of various cellular processes is possible.

Regulation of cell proliferation
through phosphorylation of:
ERα
β-catenin
MEK1
CRAF
Regulation of cell motility
through phosphorylation of:
LIMK
MLCK
Merlin
STMN1
Regulation of cell survival
through phosphorylation of:
NF-κB
BATH

Individual evidence

  1. ↑ Gary M. Bokoch: Biology of the p21-activated kinases . In: Biochemistry . 72, July 2003, pp. 743-781. doi : 10.1146 / annurev.biochem.72.121801.161742 . PMID 12676796 .
  2. ↑ a b Joachim Rudolph, James J. Crawford: Inhibitors of p21-Activated Kinases (PAKs) . In: J. Med. Chem. . 58, No. 1, November 21, 2014, pp. 111–129. doi : 10.1021 / jm501613q . PMID 25415869 .
  3. ↑ a b Jeyanthy Eswaranemail, Meera Soundararajan: UnPAKing the class differences among p21-activated kinases . In: Trends in Biochemical Sciences . 33, No. 8, August 2008. doi : 10.1016 / j.tibs.2008.06.002 . PMID 18639460 .
  4. ↑ M. Pirruccello, H. Sondermann, JG Pelton, P. Pellicena, A. Hoelz, J. Chernoff, DE Wemmer, J. Kuriyan: A dimeric kinase assembly underlying autophosphorylation in the p21 activated kinases. In: Journal of molecular biology. Volume 361, number 2, August 2006, pp. 312-326, doi : 10.1016 / j.jmb.2006.06.017 , PMID 16837009 .
  5. ^ ZS Zhao, E. Manser: PAK family kinases: Physiological roles and regulation. In: Cellular logistics. Volume 2, number 2, April 2012, pp. 59-68, doi : 10.4161 / cl.21912 , PMID 23162738 , PMC 3490964 (free full text).
  6. ^ A b Y. Baskaran, YW Ng, W. Selamat, FT Ling, E. Manser: Group I and II mammalian PAKs have different modes of activation by Cdc42. In: EMBO reports. Volume 13, number 7, June 2012, pp. 653-659, doi : 10.1038 / embor.2012.75 , PMID 22653441 , PMC 3388789 (free full text).
  7. ↑ YP Ching, VY Leong, CM Wong, HF Kung: Identification of an autoinhibitory domain of p21-activated protein kinase 5. In: The Journal of biological chemistry. Volume 278, Number 36, September 2003, pp. 33621-33624, doi : 10.1074 / jbc.C300234200 , PMID 12860998 .
  8. ↑ a b B. H. Ha, MJ Davis, C. Chen, HJ Lou, J. Gao, R. Zhang, M. Krauthammer, R. Halaban, J. Schlessinger, BE Turk, TJ Boggon: Type II p21-activated kinases (PAKs ) are regulated by an autoinhibitory pseudosubstrate. In: Proceedings of the National Academy of Sciences . Volume 109, number 40, October 2012, pp. 16107-16112, doi : 10.1073 / pnas.1214447109 , PMID 22988085 , PMC 3479536 (free full text).
  9. ↑ M. Radu, G. Semenova, R. Kosoff, J. Chernoff: PAK signaling during the development and progression of cancer. In: Nature Reviews Cancer . Volume 14, number 1, January 2014, pp. 13-25, PMID 24505617 , PMC 4115244 (free full text) (review).
  10. ↑ E. Ramos, RB Wysolmerski, RA Masaracchia: Myosin phosphorylation by human cdc42-dependent S6 / H4 kinase / gammaPAK from placenta and lymphoid cells. In: Receptors & signal transduction. Volume 7, Number 2, 1997, pp. 99-110, PMID 9392438 .
  11. ↑ TL Chew, RA Masaracchia, ZM Goeckeler, RB Wysolmerski: Phosphorylation of non-muscle myosin II regulatory light chain by p21-activated kinase (gamma-PAK). In: Journal of muscle research and cell motility. Volume 19, Number 8, November 1998, pp. 839-854, PMID 10047984 .
  12. ↑ MG Callow, p Zozulya, ML Gishizky, B. Jallal, T. Smeal: PAH4 mediates morphological changes through the regulation of GEF-H1. In: Journal of cell science. Volume 118, Pt 9 May 2005, pp. 1861-1872, doi : 10.1242 / jcs.02313 , PMID 15827085 .
  13. ↑ DC Edwards, LC Sanders, GM Bokoch, GN Gill: Activation of LIM-kinase by Pak1 couples Rac / Cdc42 GTPase signaling to actin cytoskeletal dynamics. In: Nature cell biology. Volume 1, Number 5, September 1999, pp. 253-259, doi : 10.1038 / 12963 , PMID 10559936 .
  14. ↑ S. Arber, FA Barbayannis, H. Hanser, C. Schneider, CA Stanyon, O. Bernard, P. Caroni: Regulation of actin dynamics through phosphorylation of cofilin by LIM kinase. In: Nature. Volume 393, Number 6687, June 1998, pp. 805-809, doi : 10.1038 / 31729 , PMID 9655397 .
  15. ↑ N. Yang, O. Higuchi, K. Ohashi, K. Nagata, A. Wada, K. Kangawa, E. Nishida, K. Mizuno: Cofilin phosphorylation by LIM-kinase 1 and its role in Rac-mediated actin reorganization. In: Nature. Volume 393, Number 6687, June 1998, pp. 809-812, doi : 10.1038 / 31735 , PMID 9655398 .
  16. ↑ J. Szczepanowska: Involvement of Rac / Cdc42 / PAK pathway in cytoskeletal rearrangements. In: Acta biochimica Polonica. Volume 56, Number 2, 2009, pp. 225-234, PMID 19513348 (review).
  17. ↑ RK Vadlamudi, F. Li, L. Adam, D. Nguyen, Y. Ohta, TP Stossel, R. Kumar: Filamin is essential in actin cytoskeletal assembly mediated by p21-activated kinase 1 In: Nature cell biology. Volume 4, Number 9, September 2002, pp. 681-690, doi : 10.1038 / ncb838 , PMID 12198493 .
  18. ↑ B. Dummler, K. Ohshiro, R. Kumar, J. Field: Pak protein kinases and their role in cancer. In: Cancer metastasis reviews. Volume 28, number 1-2, June 2009, pp. 51-63, doi : 10.1007 / s10555-008-9168-1 , PMID 19165420 , PMC 3923596 (free full text) (review).
  19. ↑ Rakesh Kumar, Anupama E. Gururaj, Christopher J. Barnes: p21-activated kinases in cancer . In: Nature Reviews Cancer . 6, No. 6, June 2006, pp. 459-471. doi : 10.1038 / nrc1892 . PMID 16723992 .
  20. ↑ PAK1 p21 protein (Cdc42 / Rac) -activated kinase 1 in the National Center for Biotechnology Information (NCBI). Retrieved February 7, 2016.
  21. ↑ PAK2 p21 protein (Cdc42 / Rac) -activated kinase 2 in the National Center for Biotechnology Information (NCBI). Retrieved February 7, 2016.
  22. ↑ PAK3 p21 protein (Cdc42 / Rac) -activated kinase 3 in the National Center for Biotechnology Information (NCBI). Retrieved February 7, 2016.
  23. ↑ PAK4 p21 protein (Cdc42 / Rac) -activated kinase 4 in the National Center for Biotechnology Information (NCBI). Retrieved February 7, 2016.
  24. ↑ PAK7 p21 protein (Cdc42 / Rac) -activated kinase 7 in the National Center for Biotechnology Information (NCBI). Retrieved February 7, 2016.
  25. ↑ PAK6 p21 protein (Cdc42 / Rac) -activated kinase 6 in the National Center for Biotechnology Information (NCBI). Retrieved February 7, 2016.