A5089133076- Protein Kinase Regulation and GTPase Signaling
- Enzyme Structure and Function
- Cellular transport and secretion
- Biochemical and Molecular Research
- Glycosylation and Glycoproteins Research
- Erythrocyte Function and Pathophysiology
- ATP Synthase and ATPases Research
- Cell Adhesion Molecules Research
- Endoplasmic Reticulum Stress and Disease
- Protein Tyrosine Phosphatases
- Hippo pathway signaling and YAP/TAZ
- Cellular Mechanics and Interactions
- Cancer Mechanisms and Therapy
- Melanoma and MAPK Pathways
- Vascular Malformations Diagnosis and Treatment
- Craniofacial Disorders and Treatments
- Ubiquitin and proteasome pathways
- RNA Research and Splicing
- Signaling Pathways in Disease
- Phagocytosis and Immune Regulation
- Cancer, Hypoxia, and Metabolism
- Ion channel regulation and function
- Biochemical and Structural Characterization
- Cancer-related Molecular Pathways
- Protein Structure and Dynamics
Yale University
2016-2025
Yale Cancer Center
2012
New York University
2006-2009
Uterine serous carcinoma (USC) is a biologically aggressive subtype of endometrial cancer. We analyzed the mutational landscape USC by whole-exome sequencing 57 cancers, most which were matched to normal DNA from same patients. The distribution number protein-altering somatic mutations revealed that 52 tumors had fewer than 100 (median 36), whereas 5 more 3,000 mutations. in these latter showed hallmarks defects mismatch repair. Among remainder, we found significantly increased burden...
Significance Some cancers, termed carcinosarcomas (CSs), have mixed cell types, with either epithelial or mesenchymal features. Sequencing the genomes of uterine and ovarian CSs demonstrated that these different types derive from a common precursor has many mutations typical cancers. In addition, we find tumors significant burden point amplification histone genes, suggesting potential role in sarcomatous transformation. Consistent this finding, expression specific gene carcinoma cells...
Despite advances in the diagnosis and management of idiopathic noncirrhotic portal hypertension, its pathogenesis remains elusive. Insight may be gained from study early-onset familial which Mendelian mutations account for disease. We performed exome sequencing eight subjects six kindreds with onset hypertension indeterminate etiology during infancy or childhood. Three two consanguineous families shared identical rare homozygous p.N46S mutation DGUOK, a deoxyguanosine kinase required...
The prognosis of advanced/recurrent cervical cancer patients remains poor. We analyzed 54 fresh-frozen and 15 primary cell lines, along with matched-normal DNA, by whole-exome sequencing (WES), most which harboring Human-Papillomavirus-type-16/18. found recurrent somatic missense mutations in 22 genes (including PIK3CA, ERBB2, GNAS) a widespread APOBEC cytidine deaminase mutagenesis pattern (TCW motif) both adenocarcinoma (ACC) squamous carcinomas (SCCs). Somatic copy number variants (CNVs)...
The pioneer transcription factor (TF) PU.1 controls hematopoietic cell fate by decompacting stem heterochromatin and allowing nonpioneer TFs to enter otherwise inaccessible genomic sites. deficiency fatally arrests lymphopoiesis myelopoiesis in mice, but human congenital disorders have not previously been described. We studied six unrelated agammaglobulinemic patients, each harboring a heterozygous mutation (four de novo, two unphased) of SPI1, the gene encoding PU.1. Affected patients...
Kindlins are essential FERM-domain-containing focal adhesion (FA) proteins required for proper integrin activation and signaling. Despite the widely accepted importance of each three mammalian kindlins in cell adhesion, molecular basis their function has yet to be fully elucidated, functional differences between isoforms have generally not been examined. Here, we report kindlin-2 -3 (also known as FERMT2 FERMT3, respectively); GFP-tagged localizes FAs whereas kindlin-3 does not, kindlin-2,...
Summary BRAF inhibitors improve melanoma patient survival, but resistance invariably develops. Here we report the discovery of a novel mutation that confers to PLX 4032 employing whole‐exome sequencing drug‐resistant V600K cells. We further describe new screening approach, genome‐wide piggy B ac mutagenesis screen revealed clinically relevant aberrations ( N ‐terminal truncations and CRAF overexpression). The mutation, L eu505 His substitution L505H ), is first resistance‐conferring...
Regulation of Ras GTPases by GTPase-activating proteins (GAPs) is essential for their normal signaling. Nine the ten GAPs contain a C2 domain immediately proximal to canonical GAP domain, and in RasGAP (p120GAP, p120RasGAP; RASA1 ) mutation this associated with vascular malformations humans. Here, we show that required full catalytic activity toward Ras. Analyses C2-GAP crystal structure, AlphaFold models, sequence conservation reveal direct interaction allosteric lobe. This achieved an...
RasGAP (p120RasGAP), the founding member of GTPase-activating protein (GAP) family, is one only nine human proteins to contain two SH2 domains and essential for proper vascular development. Despite its importance, interactions with key binding partners remains unclear. In this study we provide a detailed viewpoint recruitment various assess their impact on activity. We reveal generate distinct three well-known doubly phosphorylated partners: p190RhoGAP, Dok1, EphB4. Affinity measurements...
Sorting nexin 17 (SNX17) is a member of the family cytoplasmic sorting adaptor proteins that regulate endosomal trafficking cell surface proteins. SNX17 localizes to early endosomes where it directly binds NPX(Y/F) motifs in tails its target receptors mediate their rates endocytic internalization, recycling, and/or degradation. has also been implicated mediating signaling and can interact with KRIT1 (Krev interaction trapped 1), protein associated cerebral cavernous malformations, previously...
The two p190RhoGAP proteins, p190RhoGAP-A and -B, are key regulators of Rho GTPase signaling essential for actin cytoskeletal structure contractility. Here we report the discovery evolutionarily conserved GTPase-like domains located in 'middle domain', previously thought to be unstructured. Deletion these reduces RhoGAP activity. Crystal structures, MANT-GTPγS binding, thermal denaturation, biochemical assays sequence homology analysis all strongly support defects nucleotide-binding Analysis...