A5087877770- Heat shock proteins research
- ATP Synthase and ATPases Research
- Endoplasmic Reticulum Stress and Disease
- Enzyme Structure and Function
- Renal cell carcinoma treatment
- Computational Drug Discovery Methods
- Renal and related cancers
- Protein Structure and Dynamics
- Genetics, Bioinformatics, and Biomedical Research
- Plant biochemistry and biosynthesis
- Genetic and Kidney Cyst Diseases
- Ubiquitin and proteasome pathways
- Protein Tyrosine Phosphatases
- Cancer, Hypoxia, and Metabolism
- Tuberous Sclerosis Complex Research
- Mitochondrial Function and Pathology
- thermodynamics and calorimetric analyses
- Protease and Inhibitor Mechanisms
- Autophagy in Disease and Therapy
- Metabolism, Diabetes, and Cancer
- Epigenetics and DNA Methylation
- Toxin Mechanisms and Immunotoxins
- Adipose Tissue and Metabolism
- Advanced Breast Cancer Therapies
- Genetics, Aging, and Longevity in Model Organisms
SUNY Upstate Medical University
2016-2025
State University of New York
2023
Upstate University Hospital
2022
SAIC-GM (China)
2018
Cancer Research Institute
2015-2016
Article10 November 2017Open Access Source DataTransparent process Tumor suppressor Tsc1 is a new Hsp90 co-chaperone that facilitates folding of kinase and non-kinase clients Mark R Woodford Department Urology, SUNY Upstate Medical University, Syracuse, NY, USA Cancer Center, Search for more papers by this author Rebecca A Sager Biochemistry Molecular Biology, Elijah Marris Diana M Dunn Adam Blanden Ryan L Murphy Nicholas Rensing Neurology, Washington University School Medicine, St. Louis,...
Significance The activity of many proteins is dependent on molecular chaperones and their accessory proteins, cochaperones. ability a cohort kinases, which are oncogenic, to transduce signals promoted by the heat shock protein 90 (Hsp90) chaperone Cdc37 cochaperone, requires removal phosphate from phosphatase 5 (PP5). We present crystal structure PP5 with trapped in active site. reveals how can associate different substrates previously unknown determinants specificity. Our findings show...
The molecular chaperone Hsp90 protects deregulated signaling proteins that are vital for tumor growth and survival. Tumors generally display sensitivity selectivity toward inhibitors; however, the mechanism underlying this phenotype remains undefined. We report mitotic checkpoint kinase Mps1 phosphorylates a conserved threonine residue in amino-domain of Hsp90. This, turn, regulates function by reducing ATPase activity while fostering association with clients, including Mps1. Phosphorylation...
Abstract Heat shock protein-90 (Hsp90) is an essential molecular chaperone in eukaryotes involved maintaining the stability and activity of numerous signalling proteins, also known as clients. Hsp90 ATPase for its function it regulated by co-chaperones. Here we show that tumour suppressor FLCN client protein binding partners FNIP1/FNIP2 FNIPs decelerate cycle, facilitating interaction with Hsp90, consequently ensuring stability. compete activating co-chaperone Aha1 to thereby providing a...
Highlights•Stress-inducible TIMP2 is a bona fide co-chaperone of extracellular HSP90 (eHSP90)•TIMP2 regulates chaperone function and interaction with client MMP2•Secreted co-chaperones AHA1 displace each other on the eHSP90:MMP2 complex•TIMP2-AHA1 competition impacts MMP2 activity matrix gelatinolysisSummaryThe molecular heat shock protein 90 (eHSP90) stabilizes protease metalloproteinase 2 (MMP2), leading to tumor cell invasion. Although are critical modulators intracellular HSP90:client...
Highlights•Casein-kinase-2-mediated sequential phosphorylation of the co-chaperone FNIP1•FNIP1 relay leads to gradual activation Hsp90 clients•Serine/threonine protein phosphatase 5 (PP5) dephosphorylates FNIP1•O-GlcNAcylation causes ubiquitination and proteasomal degradation FNIP1SummaryThe molecular chaperone stabilizes activates client proteins. Co-chaperones post-translational modifications tightly regulate function consequently lead clients. However, it is unclear whether this process...
Abstract Protein folding quality control in cells requires the activity of a class proteins known as molecular chaperones. Heat shock protein‐90 (Hsp90), multidomain ATP driven machine, is prime representative this family proteins. Interactions between Hsp90, its co‐chaperones, and client have been shown to be important facilitating correct activation clients. Hsp90 levels functions are elevated tumor cells. Here, we computationally predict regions on native structures clients c‐Abl, c‐Src,...
Dysregulated metabolism is one of the hallmarks cancer. Under normal physiological conditions, ATP primarily generated by oxidative phosphorylation. Cancers commonly undergo a dramatic shift toward glycolysis, despite presence oxygen. This phenomenon known as Warburg effect, and requires activity LDHA. LDHA converts pyruvate to lactate in final step glycolysis often upregulated inhibitors present promising therapeutic option, blockade leads apoptosis cancer cells. Despite this, existing have...
Heat shock protein-90 (Hsp90) chaperone machinery is involved in the stability and activity of its client proteins. The function Hsp90 regulated by co-chaperones post-translational modifications. Although structural evidence exists for interaction with clients, our understanding impact toward cells remains elusive. Here, we dissect recently identified higher eukaryotic co-chaperones, FNIP1/2 (FNIPs) Tsc1, activity. Our data show that Tsc1 FNIP2 form mutually exclusive complexes FNIP1, unlike...
Cellular homeostasis relies on both the chaperoning of proteins and intracellular degradation system that delivers cytoplasmic constituents to lysosome, a process known as autophagy. The crosstalk between these processes their underlying regulatory mechanisms is poorly understood. Here, we show molecular chaperone heat shock protein 90 (Hsp90) forms complex with autophagy-initiating kinase Atg1 (yeast)/Ulk1 (mammalian), which suppresses its activity. Conversely, environmental cues lead...
More than 99% of the mitochondrial proteome is encoded by nucleus and requires refolding following import. Therefore, proteins require coordinated action molecular chaperones for their folding activation. Several heat shock protein (Hsp) chaperones, including members Hsp27, Hsp40/70, Hsp90 families, as well chaperonin complex Hsp60/10 have an established role in import folding. The 'Chaperone Code' describes regulation chaperone activity dynamic post-translational modifications; however,...
The serine/threonine protein phosphatase 5 (PP5) regulates multiple cellular signaling networks. A number of factors, including heat shock 90 (Hsp90), promote the activation PP5. However, it is unclear whether post-translational modifications also influence PP5 activity. Here, we show an "on/off switch" mechanism for regulation. casein kinase 1δ (CK1δ) phosphorylates T362 in catalytic domain PP5, which activates and enhances activity independent Hsp90. Overexpression phosphomimetic T362E-PP5...
The tissue inhibitor of metalloproteinases 2 (TIMP-2) is a specific endogenous matrix metalloproteinase (MMP-2), which key enzyme that degrades the extracellular and promotes tumor cell invasion. Although TIMP-2:MMP-2 complex controls proteolysis, signaling mechanism by two proteins associate in space remains unidentified. Here we report TIMP-2 phosphorylated outside secreted c-Src tyrosine kinase. As consequence, phosphorylation at Y90 significantly enhances potency as an MMP-2 weakens...
c-Src tyrosine kinase is a renowned key intracellular signaling molecule and potential target for cancer therapy. Secreted recent observation, but how it contributes to extracellular phosphorylation remains elusive. Using series of domain deletion mutants, we show that the N-proximal region essential its secretion. The tissue inhibitor metalloproteinases 2 (TIMP2) an substrate c-Src. Limited proteolysis-coupled mass spectrometry mutagenesis studies verify Src homology 3 (SH3) P31VHP34 motif...