PAK6

Serine/threonine-protein kinase PAK 6 is an enzyme that in humans is encoded by the PAK6 gene.^[5][6]

PAK6 belongs to the Group II PAK family members.^[7] Like other family members, PAK6 is also evolutionary conserved across species.^[8]

Discovery

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]

Gene and spliced variants

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).

Protein domains

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

Function

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]

Regulators and interactors

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]

Interactions

PAK6 has been shown to