PAK6

PAK6 Full Name

p21 protein (Cdc42/Rac)-activated kinase 6

PAK6 Introduction

p21 protein (Cdc42/Rac)-activated kinase 6 (PAK6) is a protein that in humans is encoded by the PAK6 gene. PAK6 belongs to the p21-activated kinases (PAKs) family. This family is composed by 6 family members (PAK1-6) and can be divided into two groups (group I and group II) on the basis of sequence homology and structural-functional criteria. Group I: PAK1-3; Group II: PAK4-6. PAK6 is then a member of the group II along with PAK4 and PAK5. The human PAK6 gene maps to the long arm of chromosome 15 in the region from 15q14 to 15q15. This gene spans about 38 kilobases (kb) and is composed of 16 exons. PAK6 is a protein with an approximately 75 kilodaltons (kDa) molecular weight. On the protein domain level, PAK6 presents the general characteristics of the Group II PAKs. N-terminal has a highly conserved Cdc42/Rac-interactive binding (CRIB) domain (also known as PBD, p21-binding domain) responsible for the binding of the upstream small GTPases (Cdc42, Rac, among others) that activate PAK6. On the C-terminal side, there is a highly conserved kinase catalytic domain, responsible for the enzymatic and functional activity of substrate phosphorylation. In contrast with Group I PAKs (PAK1-3), PAK6 (like other group II PAKs) does not have, as a rule, a clearly defined, functional autoinhibitory domain (AID) or a region. This may indicate that the activation mechanism of Group II PAKs, in contrast to the Group I, is absent or different and, possibly, it is in the state of "pre-active" or constitutively partially active.

As a key nodal protein in signal transduction networks, the functions of PAK6 are diverse and complex. It regulates a wide range of cellular processes by phosphorylating downstream substrates. One, PAK6 is an important regulator of steroid hormone signaling. The most thoroughly studied of these interactions is with the Androgen Receptor (AR). Both the activation of PAK6 kinase by androgen stimulation and AR-dependent recruitment of PAK6 require direct protein-protein interactions between AR and PAK6. Reciprocally, activated PAK6 phosphorylates AR. This forms a precise regulatory circuit of great importance in the physiology and pathology of androgen-dependent tissues. Second, PAK6 has been linked to cell morphology, migration, and invasion. Activation of PAK6 has been shown to promote migration and invasion abilities of certain cancer cells, including prostate cancer cells. This could be due to its ability to regulate cytoskeletal remodeling and adherens junctions and may contribute to a pro-metastatic effect during tumor progression. PAK6 also performs important functions in the nervous system. PAK6 is highly expressed in the striatum and hippocampus, which is thought to be important for neuronal migration, GABAergic interneuron function, dopaminergic neurotransmission, as well as higher cognitive and motor functions. An important discovery revealed PAK6's regulatory role in neuronal autophagy. PAK6 can promote neuronal autophagic flux by regulating the nuclear translocation of the transcription factor TFEB (Transcription Factor EB). This is a vital cellular "cleansing" mechanism crucial for clearing damaged organelles and abnormal protein aggregates, serving a protective role in maintaining neuronal health and functional homeostasis.

As for prostate cancer, PAK6 also has its complex and two-sided nature. On the other hand, more mechanistic studies have uncovered that PAK6 can also inhibit tumor growth under certain contexts. PAK6 has been reported to directly phosphorylate Androgen Receptor (AR) at serine-578 (Ser-578). This phosphorylation modification on AR negatively regulates AR's nuclear translocation, and thus blocks AR's function as a transcription factor to activate the expression of its downstream pro-growth genes. In addition, PAK6 can also induce AR's ubiquitin-mediated proteasomal degradation by phosphorylating E3 ubiquitin ligase Mdm2, which then targets AR. By these two mechanisms, PAK6 can effectively shut down the activity of AR signaling pathway, which serves as the core driving force for development and progression of the vast majority of prostate cancers. Thus, in prostate cancer, depending on the cellular context, tumor stage and crosstalk with other signaling pathways, PAK6 can play complex functions, both promoting invasion and inhibiting growth, it is thus a potential yet difficult therapeutic target and prognostic biomarker.

Figure 1. The signal transduction cascade of PAK6 in cancer. (Source: Gong CC, et al. 2020)

Alternate Names for PAK6

PAK6; p21 protein (Cdc42/Rac)-activated kinase 6; PAK5; serine/threonine-protein kinase PAK 6; p21(CDKN1A)-activated kinase 6

• 1. Ha BH, et al. Signaling, Regulation, and Specificity of the Type II p21-activated Kinases. J Biol Chem. 2015 May 22;290(21):12975-83.
  2. Gong CC, et al. PAK6: a potential anti-cancer target. Brazilian Journal of Pharmaceutical Sciences. 2020 Mar 16;56:e18315.