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Ack1 (TNK2)
ACK1 (also known as activated Cdc42-associated kinase 1 or TNK2) is a cytosolic effecter of activated transmembrane receptor tyrosine kinases (RTKs), wherein it shuttles between the cytosol and the nucleus to rapidly transduce extracellular signals from the RTKs to the intracellular effectors, recent data unfold a new aspect of its functionality as an epigenetic regulator. ACK1 gene encodes a large protein of 1038 amino acids (140 kDa) that is post-translationally modified by multiple tyrosine phosphorylations that regulate its kinase activation. The multi-domain structure of ACK1 sets it apart from other non-receptor tyrosine kinases and includes at least 8 distinct domains; the Sterile alpha motif (SAM), kinase or catalytic domain, SH3 domain, GTPase binding domain (also known as Cdc42-binding domain or CRIB domain), Clathrin interacting region, PPXY motif or WW domain interacting region, a MIG6 homology region (MHR), also known as EGFR binding domain and an ubiquitin-association (UBA) domain.
ACK1 interacts with the Estrogen Receptor (ER)/histone demethylase KDM3A (JHDM2a) complex, modifies KDM3A by tyrosine phosphorylation to regulate transcriptional outcome at HOXA1 locus to promote the growth of tamoxifen-resistant breast cancer. It is also well established that ACK1 regulates the activity of Androgen Receptor (AR) by tyrosine phosphorylation to fuel the growth of hormone-refractory prostate cancers. Further, recent explosion in genomic sequencing has revealed recurrent ACK1 gene amplification and somatic mutations in a variety of human malignancies, providing a molecular basis for its role in neoplastic transformation.With the accelerated development of potent and selective ACK1 inhibitors, targeted treatment for cancers harboring aberrant ACK1 activity may soon become a clinical reality.
References:
1.Mahajan K,et al. Oncogene. 2015 Aug 6;34(32):4162-7.
ACK1 interacts with the Estrogen Receptor (ER)/histone demethylase KDM3A (JHDM2a) complex, modifies KDM3A by tyrosine phosphorylation to regulate transcriptional outcome at HOXA1 locus to promote the growth of tamoxifen-resistant breast cancer. It is also well established that ACK1 regulates the activity of Androgen Receptor (AR) by tyrosine phosphorylation to fuel the growth of hormone-refractory prostate cancers. Further, recent explosion in genomic sequencing has revealed recurrent ACK1 gene amplification and somatic mutations in a variety of human malignancies, providing a molecular basis for its role in neoplastic transformation.With the accelerated development of potent and selective ACK1 inhibitors, targeted treatment for cancers harboring aberrant ACK1 activity may soon become a clinical reality.
References:
1.Mahajan K,et al. Oncogene. 2015 Aug 6;34(32):4162-7.
