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Kavita Shah

Bio: Kavita Shah is an academic researcher from Purdue University. The author has contributed to research in topics: Kinase & Neurodegeneration. The author has an hindex of 46, co-authored 107 publications receiving 6741 citations. Previous affiliations of Kavita Shah include University of California, San Francisco & Novartis Foundation.


Papers
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Journal ArticleDOI
23 Oct 2003-Nature
TL;DR: The identities of these substrates reveal that Cdk1 employs a global regulatory strategy involving phosphorylation of other regulatory molecules as well as phosphorylated of the molecular machines that drive cell-cycle events.
Abstract: The events of cell reproduction are governed by oscillations in the activities of cyclin-dependent kinases (Cdks). Cdks control the cell cycle by catalysing the transfer of phosphate from ATP to specific protein substrates. Despite their importance in cell-cycle control, few Cdk substrates have been identified. Here, we screened a budding yeast proteomic library for proteins that are directly phosphorylated by Cdk1 in whole-cell extracts. We identified about 200 Cdk1 substrates, several of which are phosphorylated in vivo in a Cdk1-dependent manner. The identities of these substrates reveal that Cdk1 employs a global regulatory strategy involving phosphorylation of other regulatory molecules as well as phosphorylation of the molecular machines that drive cell-cycle events. Detailed analysis of these substrates is likely to yield important insights into cell-cycle regulation.

961 citations

Journal ArticleDOI
TL;DR: The development of a protein engineering-based method to identify the direct substrates of the prototypical protein tyrosine kinase v-Src, which controls fibroblast transformation by the Rous sarcoma virus, is described.
Abstract: Protein phosphorylation plays a central role in controlling many diverse signal transduction pathways in all cells Novel protein kinases are identified at a rapid rate using homology cloning methods and genetic screens or selections; however identification of the direct substrates of kinases has proven elusive to genetic methods because of the tremendous redundancy and overlapping of substrate specificities among protein kinases We describe the development of a protein engineering-based method to identify the direct substrates of the prototypical protein tyrosine kinase v-Src, which controls fibroblast transformation by the Rous sarcoma virus To differentiate the substrates of v-Src from all other kinase substrates, we mutated the ATP binding site of v-Src such that the engineered v-Src uniquely accepted an ATP analog We show that the engineered v-Src kinase displayed catalytic efficiency with the ATP analog, N6-(cyclopentyl) ATP, which is similar to the wild-type kinase catalytic efficiency with ATP itself However, the N6-(cyclopentyl) ATP analog was not accepted by the wild-type kinase Furthermore, the engineered v-Src exhibited the same protein target specificity as wild-type v-Src despite the proximity of the reengineered nucleotide binding site to the phosphoacceptor binding site The successful engineering of v-Src’s active site to accept a unique nucleotide analog provides a unique handle by which the direct substrates of one kinase (v-Src) can be traced in the presence of any number of cellular kinases

435 citations

Journal ArticleDOI
08 Feb 2002-Cell
TL;DR: The speed and specificity of inhibition suggests that myosin-1c participates in adaptation in hair cells, the sensory cells of the inner ear.

326 citations

Journal ArticleDOI
TL;DR: The role of MAPK/ERK is established in phosphorylation-dependent cellular localization of hnRNP-K, which is required for its ability to silence mRNA translation.
Abstract: Heterogeneous nuclear ribonucleoprotein K (hnRNP-K) is one of a family of 20 proteins that are involved in transcription and post-transcriptional messenger RNA metabolism. The mechanisms that underlie regulation of hnRNP-K activities remain largely unknown. Here we show that cytoplasmic accumulation of hnRNP-K is phosphorylation-dependent. Mitogen-activated protein kinase/extracellular-signal-regulated kinase (MAPK/ERK) efficiently phosphorylates hnRNP-K both in vitro and in vivo at serines 284 and 353. Serum stimulation or constitutive activation of ERK kinase (MEK1) results in phosphorylation and cytoplasmic accumulation of hnRNP-K. Mutation at ERK phosphoacceptor sites in hnRNP-K abolishes the ability to accumulate in the cytoplasm and renders the protein incapable of regulating translation of mRNAs that have a differentiation-control element (DICE) in the 3' untranslated region (UTR). Similarly, treatment with a pharmacological inhibitor of the ERK pathway abolishes cytoplasmic accumulation of hnRNP-K and attenuates inhibition of mRNA translation. Our results establish the role of MAPK/ERK in phosphorylation-dependent cellular localization of hnRNP-K, which is required for its ability to silence mRNA translation.

288 citations

Journal ArticleDOI
TL;DR: In vivo treatment of human repopulating cells with Wnt-5A CM produced a greater proportion of phenotypically primitive hematopoietic progeny that could be isolated and shown to possess enhanced progenitor function independent of continued Wnt -5A treatment, suggesting a potential role for activation of Wnt signaling in managing patients exhibiting poor hematoplastic recovery shortly after stem cell transplantation.
Abstract: Human hematopoietic stem cells are defined by their ability to repopulate multiple hematopoietic lineages in the bone marrow of transplanted recipients and therefore are functionally distinct from hematopoietic progenitors detected in vitro. Although factors capable of regulating progenitors are well established, in vivo regulators of hematopoietic repopulating function are unknown. By using a member of the vertebrate Wnt family, Wnt-5A, the proliferation and differentiation of progenitors cocultured on stromal cells transduced with Wnt-5A or treated with Wnt-5A conditioned medium (CM) was unaffected. However, i.p. injection of Wnt-5A CM into mice engrafted with human repopulating cells increased multilineage reconstitution by >3-fold compared with controls. Furthermore, in vivo treatment of human repopulating cells with Wnt-5A CM produced a greater proportion of phenotypically primitive hematopoietic progeny that could be isolated and shown to possess enhanced progenitor function independent of continued Wnt-5A treatment. Our study demonstrates that Wnt-5A augments primitive hematopoietic development in vivo and represents an in vivo regulator of hematopoietic stem cell function in the human. Based on these findings, we suggest a potential role for activation of Wnt signaling in managing patients exhibiting poor hematopoietic recovery shortly after stem cell transplantation.

249 citations


Cited by
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Journal ArticleDOI
TL;DR: Observations to date suggest that oxidative stress, chronic inflammation, and cancer are closely linked.

3,922 citations

Journal ArticleDOI
14 Apr 2005-Nature
TL;DR: Insights gained from understanding how the Wnt pathway is integrally involved in both stem cell and cancer cell maintenance and growth in the intestinal, epidermal and haematopoietic systems may serve as a paradigm for understanding the dual nature of self-renewal signals.
Abstract: The canonical Wnt cascade has emerged as a critical regulator of stem cells. In many tissues, activation of Wnt signalling has also been associated with cancer. This has raised the possibility that the tightly regulated self-renewal mediated by Wnt signalling in stem and progenitor cells is subverted in cancer cells to allow malignant proliferation. Insights gained from understanding how the Wnt pathway is integrally involved in both stem cell and cancer cell maintenance and growth in the intestinal, epidermal and haematopoietic systems may serve as a paradigm for understanding the dual nature of self-renewal signals.

3,625 citations

Journal ArticleDOI
07 Jan 2000-Cell
TL;DR: The important findings in the history of signal transduction are adequately covered in many reviews, and I have therefore cited reviews that discuss the seminal papers.

2,491 citations

Journal ArticleDOI
16 Jul 2004-Science
TL;DR: BMS-354825 is an orally bioavailable ABL kinase inhibitor with two-log increased potency relative to imatinib that retains activity against 14 of 15 imatinIB-resistant BCR-ABL mutants and illustrates how molecular insight into kinase inhibitors resistance can guide the design of second-generation targeted therapies.
Abstract: Resistance to the ABL kinase inhibitor imatinib (STI571 or Gleevec) in chronic myeloid leukemia (CML) occurs through selection for tumor cells harboring BCR-ABL kinase domain point mutations that interfere with drug binding. Crystallographic studies predict that most imatinib-resistant mutants should remain sensitive to inhibitors that bind ABL with less stringent conformational requirements. BMS-354825 is an orally bioavailable ABL kinase inhibitor with two-log increased potency relative to imatinib that retains activity against 14 of 15 imatinib-resistant BCR-ABL mutants. BMS-354825 prolongs survival of mice with BCR-ABL-driven disease and inhibits proliferation of BCR-ABL-positive bone marrow progenitor cells from patients with imatinib-sensitive and imatinib-resistant CML. These data illustrate how molecular insight into kinase inhibitor resistance can guide the design of second-generation targeted therapies.

1,812 citations

Journal ArticleDOI
TL;DR: A facile approach for designing families of GPCRs with engineered ligand specificities will prove to be powerful tools for selectively modulating signal-transduction pathways in vitro and in vivo.
Abstract: We evolved muscarinic receptors in yeast to generate a family of G protein-coupled receptors (GPCRs) that are activated solely by a pharmacologically inert drug-like and bioavailable compound (clozapine-N-oxide) Subsequent screening in human cell lines facilitated the creation of a family of muscarinic acetylcholine GPCRs suitable for in vitro and in situ studies We subsequently created lines of telomerase-immortalized human pulmonary artery smooth muscle cells stably expressing all five family members and found that each one faithfully recapitulated the signaling phenotype of the parent receptor We also expressed a Gi-coupled designer receptor in hippocampal neurons (hM4D) and demonstrated its ability to induce membrane hyperpolarization and neuronal silencing We have thus devised a facile approach for designing families of GPCRs with engineered ligand specificities Such reverse-engineered GPCRs will prove to be powerful tools for selectively modulating signal-transduction pathways in vitro and in vivo

1,696 citations