Research Overview

A major interest in our lab is to determine how tyrosine phosphorylation regulates epigenetic processes that affect cellular homeostasis and cancer cell survival. We employ multiple tyrosine kinases to investigate these processes. The examples are:

WEE1 : As an epigenetic modulator

ACK1 : Oncogene in breast, prostate, lung and pancreatic cancers

Some of the major findings of our lab include:

• We demonstrated for the first time that WEE1 kinase is an epigenetic modifier; it phosphorylated histone H2B at Tyrosine 37 specifically in late S phase of cell cycle, upstream of major histone loci Hist1.

• H2B Tyr37-phosphorylation suppressed transcription of all the core and linker histones, thus maintaining equimolar ratio of DNA to histones at the end of S phase.

• We demonstrated that ACK1 activation is present in various tumors, including prostate, breast and pancrreatic cancers. The addiction to ACK1 signaling was validated by a small molecule inhibitor, AIM-100, which not only inhibited ACK1 signaling but also suppressed cancer cell growth.

• We identified a novel phosphorylation site, Tyrosine 176, in AKT. AKT Tyr176- phosphorylation correlated with breast and pancreatic cancer progression to metastatic stages.

• Androgen receptor (AR) was identified to be ACK1 substrate. The Tyr267-phosphorylated AR initiated a distinct trasncriptional program which was critical for androgen-independent growth of prostate cancer (also called as CRPC).

 



Mahajan K et al. J. Cell. Physiol. 224: 327-333, 2010.

Current Projects
• WEE1-H2B epigenetic signaling in cancers
• Characerization of ACK1/TNK2 knockout mice to assess ACK1/AKT signaling
• Identification of novel WEE1, ACK1 and AKT allosteric inhibitors
• Role of ACK1/AR signaling in radioresistant prostate cancer

Postdoctoral Opportunities


We are currently interested in hiring two postdoctoral fellows and research associates in our lab, If interested, please send your CV at


Nupam.mahajan@moffitt.org

 

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