La Jolla Salk Institute

La Jolla, CA, United States

La Jolla Salk Institute

La Jolla, CA, United States

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Lopez-Otin C.,University of Oviedo | Hunter T.,La Jolla Salk Institute
Nature Reviews Cancer | Year: 2010

Kinases and proteases are responsible for two fundamental regulatory mechanisms phosphorylation and proteolysis that orchestrate the rhythms of life and death in all organisms. Recent studies have highlighted the elaborate interplay between both post-translational regulatory systems. Many intracellular or pericellular proteases are regulated by phosphorylation, whereas multiple kinases are activated or inactivated by proteolytic cleavage. The functional consequences of this regulatory crosstalk are especially relevant in the different stages of cancer progression. What are the clinical implications derived from the fertile dialogue between kinases and proteases in cancer?

Lemke G.,La Jolla Salk Institute
Cold Spring Harbor Perspectives in Biology | Year: 2013

The TAM receptors-Tyro3, Axl, and Mer-comprise a unique family of receptor tyrosine kinases, in that as a group they play no essential role in embryonic development. Instead, they function as homeostatic regulators in adult tissues and organ systems that are subject to continuous challenge and renewal throughout life. Their regulatory roles are prominent in the mature immune, reproductive, hematopoietic, vascular, and nervous systems. The TAMs and their ligands-Gas6 and Protein S-are essential for the efficient phagocytosis of apoptotic cells and membranes in these tissues; and in the immune system, theyact as pleiotropic inhibitors of the innate inflammatory response to pathogens. Deficiencies in TAM signaling are thought to contribute to chronic inflammatory and autoimmune disease in humans, and aberrantly elevated TAMsignaling is strongly associated with cancer progression, metastasis, and resistance to targeted therapies. © 2013 Cold Spring Harbor Laboratory Press; all rights reserved.

Verma I.M.,La Jolla Salk Institute
Science | Year: 2013

Gene therapy trials show a beneficial effect in children suffering from a neurodegenerative disorder or an immunodeficiency disease.

Rothlin C.V.,Yale University | Lemke G.,La Jolla Salk Institute
Current Opinion in Immunology | Year: 2010

The TAM receptor tyrosine kinases Tyro3, Axl, and Mer and their ligands Gas6 and Protein S are essential for the phagocytosis of apoptotic cells and membranes in the adult immune, nervous, and reproductive systems. Genetic studies indicate that this receptor-ligand system is central to apoptotic cell engulfment that is triggered by the 'eat-me' signal phosphatidylserine (PtdSer). At the same time, TAM signaling is normally activated by Toll-like receptor (TLR) and type I interferon signaling, as part of the innate inflammatory response in dendritic cells (DCs) and macrophages, where it inhibits this response. Deficiencies in TAM signaling result in human retinal dystrophies and may contribute to lupus and other human autoimmune diseases. © 2010 Elsevier Ltd.

Bellin M.,Leiden University | Marchetto M.C.,La Jolla Salk Institute | Gage F.H.,La Jolla Salk Institute | Mummery C.L.,Leiden University
Nature Reviews Molecular Cell Biology | Year: 2012

Worldwide increases in life expectancy have been paralleled by a greater prevalence of chronic and age-associated disorders, particularly of the cardiovascular, neural and metabolic systems. This has not been met by commensurate development of new drugs and therapies, which is in part owing to the difficulty in modelling human diseases in laboratory assays or experimental animals. Patient-specific induced pluripotent stem (iPS) cells are an emerging paradigm that may address this. Reprogrammed somatic cells from patients are already applied in disease modelling, drug testing and drug discovery, thus enabling researchers to undertake studies for treating diseases 'in a dish', which was previously inconceivable. © 2012 Macmillan Publishers Limited. All rights reserved.

Stevens C.F.,La Jolla Salk Institute
Proceedings of the National Academy of Sciences of the United States of America | Year: 2015

The primary visual cortex is organized in a way that assigns a specific collection of neurons the job of providing the rest of the brain with all of the information it needs about each small part of the image present on the retina: Neighboring patches of the visual cortex provide the information about neighboring patches of the visual world. Each one of these cortical patches-often identified as a "pinwheel"-contains thousands of neurons, and its corresponding image patch is centered on a particular location in the retina. For stimuli within their image patch, neurons respond selectively to lines or edges with a particular slope (orientation tuning) and to regions of the patch of different sizes (known as spatial frequency tuning). The same number of neurons is devoted to reporting each possible slope (orientation). For the cells that cover different-sized regions of their image patch, however, the number of neurons assigned depends strongly on their preferred region size. Only a few neurons report on large and small parts of the image patch, but many neurons report visual information from medium-sized areas. I show here that having different numbers of neurons responsible for image regions of different sizes actually carries out a computation: Edges in the image patch are extracted. I also explain how this edge-detection computation is done.

Liu F.,La Jolla Salk Institute | Xia Y.,La Jolla Salk Institute | Parker A.S.,La Jolla Salk Institute | Verma I.M.,La Jolla Salk Institute
Immunological Reviews | Year: 2012

The inhibitor of nuclear factor-κB (IκB) kinase (IKK) complex is the master regulator of the NF-κB signaling pathway. The activation of the IKK complex is a tightly regulated, highly stimulus-specific, and target-specific event that is essential for the plethora of functions attributed to NF-κB. More recently, NF-κB-independent roles of IKK members have brought increased complexity to its biological function. This review highlights some of the major advances in the studies of the process of IKK activation and the biological roles of IKK family members, with a focus on NF-κB-independent functions. Understanding these complex processes is essential for targeting IKK for therapeutics. © 2012 John Wiley & Sons A/S.

Alcohol stimulates the hypothalamic-pituitary-adrenal (HPA) axis through brain-based mechanisms in which endogenous corticotropin-releasing factor (CRF) plays a major role. This review first discusses the evidence for this role, as well as the possible importance of intermediates such as vasopressin, nitric oxide and catecholamines. We then illustrate the long-term influence exerted by alcohol on the HPA axis, such as the ability of a first exposure to this drug during adolescence, to permanently blunt neuroendocrine responses to subsequent exposure of the drug. In view of the role played by CRF in addiction, it is likely that a better understanding of the mechanisms through which this drug stimulates the HPA axis may lead to the development of new therapies used in the treatment of alcohol abuse, including clinically relevant CRF antagonists. © 2014.

Rivier J.E.,La Jolla Salk Institute | Rivier C.L.,La Jolla Salk Institute
Frontiers in Neuroendocrinology | Year: 2014

Elusive for more than half a century, corticotropin-releasing factor (CRF) was finally isolated and characterized in 1981 from ovine hypothalami and shortly thereafter, from rat brains. Thirty years later, much has been learned about the function and localization of CRF and related family members (Urocortins 1, 2 and 3) and their 2 receptors, CRF receptor type 1 (CRFR1) and CRF receptor type 2 (CRFR2). Here, we report the stepwise development of peptide CRF agonists and antagonists, which led to the CRFR1 agonist Stressin1; the long-acting antagonists Astressin2-B which is specific for CRFR2; and Astressin B, which binds to both CRFR1 and CRFR2.This analog has potential for the treatment of CRF-dependent diseases in the periphery, such as irritable bowel syndrome. © 2013 Elsevier Inc.

Vacik T.,La Jolla Salk Institute | Stubbs J.L.,La Jolla Salk Institute | Lemke G.,La Jolla Salk Institute
Genes and Development | Year: 2011

Axial patterning of the embryonic brain requires a precise balance between canonical Wnt signaling, which dorsalizes the nervous system, and Sonic hedgehog (Shh), which ventralizes it. The ventral anterior homeobox (Vax) transcription factors are induced by Shh and ventralize the forebrain through a mechanism that is poorly understood. We therefore sought to delineate direct Vax target genes. Among these, we identify an extraordinarily conserved intronic region within the gene encoding Tcf7l2, a key mediator of canonical Wnt signaling. This region functions as a Vax2-activated internal promoter that drives the expression of dnTcf7l2, a truncated Tcf7l2 isoform that cannot bind β-catenin and that therefore acts as a potent dominant-negative Wnt antagonist. Vax2 concomitantly activates the expression of additional Wnt antagonists that cooperate with dnTcf7l2. Specific elimination of dnTcf7l2 in Xenopus results in headless embryos, a phenotype consistent with a fundamental role for this regulator in forebrain development.

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