1.ACK1 tyrosine kinase interacts with histone demethylase KDM3A to regulate the mammary tumor oncogene HOXA1.
Mahajan K1, Lawrence HR2, Lawrence NJ2, Mahajan NP3. J Biol Chem. 2014 Oct 10;289(41):28179-91. doi: 10.1074/jbc.M114.584425. Epub 2014 Aug 22.
Hormone therapy with the selective estrogen-receptor modulator tamoxifen provides a temporary relief for patients with estrogen receptor α (ER)-positive breast cancers. However, a subset of patients exhibiting overexpression of the HER2 receptor tyrosine kinase displays intrinsic resistance to tamoxifen therapy. Therefore, elucidating the mechanisms promoting the estrogen (E2)-independent ER-regulated gene transcription in tamoxifen-resistant breast tumors is essential to identify new therapeutic avenues to overcome drug resistance and ameliorate poor prognosis. The non-receptor tyrosine kinase, ACK1 (also known as TNK2), has emerged as a major integrator of signaling from various receptor tyrosine kinases including HER2. We have uncovered that heregulin-mediated ACK1 activation promoted ER activity in the presence of tamoxifen, which was significantly down-regulated upon ACK1 knockdown or inhibition of ACK1 by small molecule inhibitors, AIM-100 or Dasatinib.
2.Effect of Ack1 tyrosine kinase inhibitor on ligand-independent androgen receptor activity.
Mahajan K1, Challa S, Coppola D, Lawrence H, Luo Y, Gevariya H, Zhu W, Chen YA, Lawrence NJ, Mahajan NP. Prostate. 2010 Sep 1;70(12):1274-85. doi: 10.1002/pros.21163.
BACKGROUND: Androgen receptor (AR) plays a critical role in the progression of both androgen-dependent and androgen-independent prostate cancer (AIPC). Ligand-independent activation of AR in AIPC or castration resistant prostate cancer (CRPC) is often associated with poor prognosis. Recently, tyrosine kinase Ack1 has been shown to regulate AR activity by phosphorylating it at tyrosine 267 and this event was shown to be critical for AIPC growth. However, whether a small molecule inhibitor that can mitigate Ack1 activation is sufficient to abrogate AR activity on AR regulated promoters in androgen-depleted environment is not known.
3.Ack1-mediated androgen receptor phosphorylation modulates radiation resistance in castration-resistant prostate cancer.
Mahajan K1, Coppola D, Rawal B, Chen YA, Lawrence HR, Engelman RW, Lawrence NJ, Mahajan NP. J Biol Chem. 2012 Jun 22;287(26):22112-22. doi: 10.1074/jbc.M112.357384. Epub 2012 May 7.
Androgen deprivation therapy has been the standard of care in prostate cancer due to its effectiveness in initial stages. However, the disease recurs, and this recurrent cancer is referred to as castration-resistant prostate cancer (CRPC). Radiotherapy is the treatment of choice; however, in addition to androgen independence, CRPC is often resistant to radiotherapy, making radioresistant CRPC an incurable disease. The molecular mechanisms by which CRPC cells acquire radioresistance are unclear. Androgen receptor (AR)-tyrosine 267 phosphorylation by Ack1 tyrosine kinase (also known as TNK2) has emerged as an important mechanism of CRPC growth. Here, we demonstrate that pTyr(267)-AR is recruited to the ATM (ataxia telangiectasia mutated) enhancer in an Ack1-dependent manner to up-regulate ATM expression. Mice engineered to express activated Ack1 exhibited a significant increase in pTyr(267)-AR and ATM levels. Furthermore, primary human CRPCs with up-regulated activated Ack1 and pTyr(267)-AR also exhibited significant increase in ATM expression.
4.Ack1 tyrosine kinase activation correlates with pancreatic cancer progression.
Mahajan K1, Coppola D, Chen YA, Zhu W, Lawrence HR, Lawrence NJ, Mahajan NP. Am J Pathol. 2012 Apr;180(4):1386-93. doi: 10.1016/j.ajpath.2011.12.028. Epub 2012 Feb 7.
Pancreatic cancer is a significant cause of cancer mortality worldwide as the disease has advanced significantly in patients before symptoms are evident. The signal transduction pathways that promote this rapid progression are not well understood. Ack1 or TNK2, an ubiquitously expressed oncogenic non-receptor tyrosine kinase, integrates signals from ligand-activated receptor tyrosine kinases to modulate intracellular signaling cascades. In the present study, we investigated the Ack1 activation profile in a pancreatic cancer tumor microarray, and observed that expression levels of activated Ack1 and pTyr284-Ack1 positively correlated with the severity of disease progression and inversely correlated with the survival of patients with pancreatic cancer. To explore the mechanisms by which Ack1 promotes tumor progression, we investigated the role of AKT/PKB, an oncogene and Ack1-interacting protein. Ack1 activates AKT directly in pancreatic and other cancer cell lines by phosphorylating AKT at Tyr176 to promote cell survival.