1. S-7 : A new cytokine receptor activation paradigm: Activation of JAK2 by the growth hormone receptor

    Cytokine 70(1):22 (2014)

    The conformational changes required to transmit the GH binding signal from the extracellular domain of the GH receptor to its intracellular domain resulting in activation of JAK2 has been enigmatic. We have recently defined the first complete mechanistic model for JAK2 activation based...
  2. Increased Polyubiquitination and Proteasomal Degradation of a Munc18-1 Disease-Linked Mutant Causes Temperature-Sensitive Defect in Exocytosis

    Cell Reports 9(1):206 (2014) PMID 25284778

    Munc18-1 is a critical component of the core machinery controlling neuroexocytosis. Recently, mutations in Munc18-1 leading to the development of early infantile epileptic encephalopathy have been discovered. However, which degradative pathway controls Munc18-1 levels and how it impact...
  3. Pleckstrin homology domain leucine-rich repeat protein phosphatases set the amplitude of receptor tyrosine kinase output.

    PNAS 111(38):E3957 (2014) PMID 25201979 PMCID PMC4183331

    Growth factor receptor levels are aberrantly high in diverse cancers, driving the proliferation and survival of tumor cells. Understanding the molecular basis for this aberrant elevation has profound clinical implications. Here we show that the pleckstrin homology domain leucine-rich repeat prot...
  4. Rapid mapping of interactions between Human SNX-BAR proteins measured in vitro by AlphaScreen and single-molecule spectroscopy.

    Molecular & Cellular Proteomics 13(9):2233 (2014) PMID 24866125 PMCID PMC4159646

    Protein dimerization and oligomerization is commonly used by nature to increase the structural and functional complexity of proteins. Regulated protein assembly is essential to transfer information in signaling, transcriptional, and membrane trafficking events. Here we show that a combination of...
  5. Biochemical characterization of the phosphatase domain of the tumor suppressor PH domain leucine-rich repeat protein phosphatase.

    Biochemistry (Washington) 53(24):3971 (2014) PMID 24892992 PMCID PMC4072346

    PH domain leucine-rich repeat protein phosphatase (PHLPP) directly dephosphorylates and inactivates Akt and protein kinase C and is therefore a prime target for pharmacological intervention of two key signaling pathways, the phosphatidylinositol 3-kinase and diacylglycerol signaling pathways. He...
  6. Both decreased and increased SRPK1 levels promote cancer by interfering with PHLPP-mediated dephosphorylation of Akt.

    Molecular Cell 54(3):378 (2014) PMID 24703948 PMCID PMC4019712

    Akt activation is a hallmark of human cancers. Here, we report a critical mechanism for regulation of Akt activity by the splicing kinase SRPK1, a downstream Akt target for transducing growth signals to regulate splicing. Surprisingly, we find that SRPK1 has a tumor suppressor function because a...
  7. Cortactin scaffolds Arp2/3 and WAVE2 at the epithelial zonula adherens.

    Journal of Biological Chemistry 289(11):7764 (2014) PMID 24469447 PMCID PMC3953287

    Cadherin junctions arise from the integrated action of cell adhesion, signaling, and the cytoskeleton. At the zonula adherens (ZA), a WAVE2-Arp2/3 actin nucleation apparatus is necessary for junctional tension and integrity. But how this is coordinated with cadherin adhesion is not known. We now...
  8. Single-molecule analysis reveals self assembly and nanoscale segregation of two distinct cavin subcomplexes on caveolae.

    eLife 3:e01434 (2014) PMID 24473072 PMCID PMC3903133

    In mammalian cells three closely related cavin proteins cooperate with the scaffolding protein caveolin to form membrane invaginations known as caveolae. Here we have developed a novel single-molecule fluorescence approach to directly observe interactions and stoichiometries in protein complexes...
  9. Guide to virtual screening: application to the Akt phosphatase PHLPP.

    Methods in Molecular Biology 819:561 (2012) PMID 22183558

    We present an example-based description of virtual screening (VS) techniques used to identify new regulators of the Akt phosphatase PHLPP (PH domain Leucine repeat Protein Phosphatase). This enzyme opposes the effects of two kinases, Akt and PKC, which play a major role in cell growth and surviv...
  10. Discovery of small molecule inhibitors of the PH domain leucine-rich repeat protein phosphatase (PHLPP) by chemical and virtual screening.

    Journal of medicinal and pharmaceutical chemistry 53(19):6899 (2010) PMID 20836557 PMCID PMC2951065

    PH domain Leucine-rich repeat protein phosphatase (PHLPP) directly dephosphorylates and inactivates Akt and protein kinase C, poising it as a prime target for pharmacological intervention of two major survival pathways. Here we report on the discovery of small molecule inhibitors of the phosphat...
  11. Variation of the lateral mobility of transmembrane peptides with hydrophobic mismatch.

    Journal of Physical Chemistry B 114(10):3559 (2010) PMID 20170092

    A hydrophobic mismatch between protein length and membrane thickness can lead to a modification of protein conformation, function, and oligomerization. To study the role of hydrophobic mismatch, we have measured the change in mobility of transmembrane peptides possessing a hydrophobic helix of v...
  12. Asymmetric alpha-alkynylation of piperidine via N-sulfinyliminium salts.

    Journal of Organic Chemistry 72(13):4882 (2007) PMID 17523673

    Piperidine was stereoselectively alpha-alkynylated in a four-step sequence made up of transformation to a chiral nonracemic N-sulfinylpiperidine, anodic oxidation to N-sulfinyliminium ion equivalent, alkynylation through addition of a mixed organoaluminum derivative, and final acidic deprotectio...
  13. PHLPP and a second isoform, PHLPP2, differentially attenuate the amplitude of Akt signaling by regulating distinct Akt isoforms.

    Molecular Cell 25(6):917 (2007) PMID 17386267

    Akt/protein kinase B controls cell growth, proliferation, and survival. We recently discovered a novel phosphatase PHLPP, for PH domain leucine-rich repeat protein phosphatase, which terminates Akt signaling by directly dephosphorylating and inactivating Akt. Here we describe a second family mem...
  14. PHLPP and a Second Isoform, PHLPP2, Differentially Attenuate the Amplitude of Akt Signaling by Regulating Distinct Akt Isoforms

    Molecular Cell 25(6):917 (2007)

    Akt/protein kinase B controls cell growth, proliferation, and survival. We recently discovered a novel phosphatase PHLPP, for PH domain leucine-rich repeat protein phosphatase, which terminates Akt signaling by directly dephosphorylating and inactivating Akt. Her...
  15. Diastereoselective α-allylation of secondary amines

    Tetrahedron (2006)

    We describe the diastereoselective α-allylation of various amines using an anodic oxidation-amidoalkylation sequence. Especially, we found that an acyclic amine, diethylamine, can be allylated with an excellent diastereoselectivity, as high as 94/6. Following our simple protocol, functional...
  16. Anodic oxidation of chiral sulfinylamines: a new route to highly diastereoselective α-alkylation of piperidine

    Tetrahedron Letters 46(31):5131 (2005)