PAK6

The PAK6 was originally cloned as an androgen receptor interacting kinase which can be stimulated by androgen receptor but not Rac or Cdc42, like other family members.[7]

The human PAK6 gene consists of 16 exons of which 8 exons are used for 5’-UTR splicing to generating 17 transcripts by alternative splicing, and the gene is about 38-kb long. Among PAK6 transcripts, 14 are protein coding RNAs to code four proteins of 681 and 636 amino acids while remaining PAK6 transcripts are non-coding RNAs. There are five transcripts in murine PAK6 gene, of which two transcripts are protein coding and other two non-coding RNAs(Gene from review).

Following the general structural organization of the group II PAKs, PAK6 also contains a kinase, and a GTPase interacting domain.[9][10]

This gene encodes a protein that shares a high degree of sequence similarity with p21-activated kinase (PAK) family members. The proteins of this family are Rac/Cdc42-associated Ste20-like Ser/Thr protein kinases, characterized by a highly conserved amino-terminal Cdc42/Rac interactive binding (CRIB) domain and a carboxyl-terminal kinase domain. PAK kinases are implicated in the regulation of a number of cellular processes, including cytoskeleton rearrangement, apoptosis and the MAP kinase signaling pathway. The protein encoded by this gene was found to interact with androgen receptor (AR), which is a steroid hormone-dependent transcription factor that is important for male sexual differentiation and development. The p21-activated protein kinase 6 gene was found to be highly expressed in testis and prostate tissues and the encoded protein was shown to cotranslocate into the nucleus with AR in response to androgen.[6]

Genetic deletion of PAK6 alone in mice leads to increased body mass.[11] However, PAK6 deletion along with PAK5 impairs the ability of animals to learn and move.[11][12] PAK6 expression is increased in a rat model of spinal cord injury.[13] PAK6 is also considered a candidate gene for epileptic encephalopathy,[14] and interacts with Parkinson associated gene product leucine-rich repeat kinase 2.[15] PAK6 expression has been found to be overexpressed in prostate cancer,[16][17] hepatocellular carcinoma,[18] and colon cancer.[19] PAK6 levels have been correlated well with therapeutic resistance to 5-flurouracil,[19] docetaxel,[17] and radiation.[20]

PAK6 kinase activity is positively regulated by androgen receptor,[7][21] p38MAPK,[22] 5-fluorouracil[19] and atypical Rho family GTPase Chp/RhoV.[23] PAK6 expression is negatively regulated by miR-328, miR-429 and miR-23a.[24][25][26] PAK6 interacts with junctional protein IQGAP1,[27][28] E3 ligase Mdm2,[29] and leucine-rich repeat kinase 2 (LRRK2).[15]

PAK6 has been shown to interact with Androgen receptor.[5][7]