Current Research

The Chaperone Code

Heat shock protein 90 (Hsp90) is an evolutionarily conserved molecular chaperone that is involved in the stability and activation of at least 300 proteins, also known as clients, under normal cellular conditions. The Hsp90 clients participate in the full breadth of cellular processes, including cell growth and cell cycle control, signal transduction, DNA repair, transcription, and many others. Hsp90 chaperone function is coupled to its ability to bind and hydrolyze ATP, which is tightly regulated both by co-chaperone proteins and post-translational modifications (PTMs). Many reported PTMs of Hsp90 alter chaperone function and consequently affect myriad cellular processes. Here, we review the contributions of PTMs, such as phosphorylation, acetylation, SUMOylation, methylation, O-GlcNAcylation, ubiquitination, and others, toward regulation of Hsp90 function. We also discuss how the Hsp90 modification state affects cellular sensitivity to Hsp90-targeted therapeutics that specifically bind and inhibit its chaperone activity. The ultimate challenge is to decipher the comprehensive and combinatorial array of PTMs that modulate Hsp90 chaperone function, a phenomenon termed the “chaperone code.”

 
Kidney Cancer

 Worldwide nearly 338,000 people develop kidney cancer every year, and over 100,000 people die from the disease. Renal cell carcinoma (RCC) is the most common type of chemotherapy-resistant kidney cancer and it is distinguishable by histopathological features as well as the underlying gene mutations. The most common type of RCC, clear cell renal cell carcinoma (ccRCC), is closely associated with the mutations of the Von Hippel-Lindau (VHL) tumor suppressor gene that lead to stabilization of hypoxia inducible factors (HIF-1α and HIF-2α), which is critical for tumor growth and angiogenesis in both sporadic and familial forms of this disease.

 

VHL also possess multiple HIF-independent functions. Our laboratory uses a combination of cell-based assays, biochemical, biophysical assays, tumors derived from ccRCC patients and tumor xenografts to investigate the role of post-translational modifications of Hsp90 and its co-chaperones in chaperoning the signaling pathways that maybe involved in ccRCC initiation and progression. 

Simplified representation of the kidney cancer gene pathways

Birt-Hogg-Dubé (BHD) &
Tuberous Sclerosis Complex (TSC) Syndromes

Germline mutations in the tumor suppressor gene FLCN cause Birt-Hogg-Dubé (BHD) syndrome, which shares many phenotypic manifestations with Tuberous Sclerosis Complex (TSC) due to TSC1 or TSC2 mutations. The exact molecular function of FNIP1/2 (binding partners of Flcn)  and Tsc1, however, had remained elusive. Our work demonstrated that FNIP1/2 and Tsc1 are new co-chaperones of Hsp90. This research establishes an active role for Tsc1 and FNIP1 as facilitators of Hsp90-mediated folding of kinase and non-kinase clients – including Tsc2 and FLCN – thereby preventing their ubiquitination and degradation.

Current literatures describe FNIP1/2 and Tsc1 as negative regulators of AMPK/mTOR signaling. As a consequence, the vast majority of the field has focused solely on this single pathway, where as we have demonstrated the ubiquity of FNIP1/2 and Tsc1 across a variety of signaling pathways. In fact it is likely their roles as suppressors of mTOR are a function of their roles as Hsp90 co-chaperones.

 

Understanding the independent roles of FNIP1/2 and Tsc1 will aid in the development of targeted therapies for tuberous sclerosis and Birt-Hogg-Dubé syndromes alone or in concert with Hsp90 inhibitors.

 

 

Hsp90

mollapom@upstate.edu

(315)464-8749

Departments of Urology &

Biochemistry and Molecular Biology

Upstate Medical University

766 Irving Ave

Syracuse, NY 13210