We employ two tyrosine kinases, WEE1 and Ack1 (TNK2) to investigate signaling and epigenetic processes.
Some of the major findings of our lab include:
- We demonstrated for the first time that WEE1 kinase is an epigenetic modifier; it phosphorylates histone H2B at Tyrosine 37 in a cell cycle dependent manner.
- H2B Ty37-phosphorylation suppressed transcription of all core and linker histones, maintaining equimolar ratio of DNA to histones at the end of S phase.
- WEE1 mediated H2B Tyr37-phosphorylation acts as a switch to initiate transcriptional shutdown by recruiting repressors like HIRA and excluding the coactivator NPAT and RNA Pol II.
- We demonstrated that Ack1 is activated in various tumors, including prostate, breast and pancreatic cancer. We identified multiple effectors of Ack1 signaling; AR, AKT, ATM and Wwox.
- Addiction of cancerous cells to Ack1 signaling was validated by a small molecular inhibitor, AIM-100.
- We identified a novel phosphorylation site, Tyrosine 176, in AKT. AKT Tyr176-phosphyrlation correlates with breast, lung and pancreatic cancer progression to metastatic stages.
- the Tyr267-phosphorylated AR initiated a distinct transcriptional program, critical for androgen-independent growth of prostate cancer (also called CRPC) and promotes radioresistance.