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Open Access Publications from the University of California

UCSD Molecule Pages

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The UCSD Signaling Gateway Molecule Pages, part of the Signaling Gateway project, provide essential information on over thousands of proteins involved in cellular signaling. Each Molecule Page contains regularly updated information derived from public data sources as well as sequence analysis, references and links to other databases. Published Molecule Pages contain an expert-authored review article that describes the biological activity, regulation and localization of the protein.

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A peer reviewed journal with structured data

The Molecule Pages from UCSD Signaling Gateway have been regularly published online since one decade and are now printed biannually. As a researcher involved in biomathematical and biomechanical modeling and simulation, I found these pages very informative, either when dealing with biological processes happening at the nano- and microscopic scales, or incorporating these events in a meso- and macroscopic scale modeling to enhance reductionist models when necessary. UCSD Molecule Pages indeed yield information that enables interdisciplinary research and I have cited the Molecule Pages over 130 times in my recent book ‘Intracellular Signaling Mediators in the Circulatory and Ventilatory Systems’ (Springer New York, 2013).


p38 beta MAP kinase

In mammals, there are four p38 protein kinases: p38α, p38β, p38γ and p38δ. p38β was identified in 1996 as a closely related protein kinase of p38α, sharing 74% sequence identity and the Thr-Gly-Tyr dual phosphorylation motif characteristic of all p38 MAPKs. p38β is widely distributed in cells and tissues, but less so than p38α; p38β is particularly abundant in endothelial cells. p38β is activated in vivo by dual phosphorylation at Thr180 and Tyr182 by the MAP2K, MKK3 and MKK6 in response to a multitude of stimuli including environmental stressors, cytokines and growth factors. p38β can be dephosphorylated on both its Thr and Tyr residues by Dual-Specificity Phosphatases. p38β, like p38α, is targeted by a class of pyridinyl imidazole drugs that do not target the other two p38 MAPKs. These compounds were invaluable in discovering functions regulated by p38α and p38β. However, they do not permit to distinguish functions mediated by p38β from those regulated by p38α. This distinction has been made possible by the use of genetically engineered mice. p38β-deficient mice are not embryonic lethal such as those lacking p38α. However ectopic expression of p38β can rescue the lethality of p38α-deficiency. This suggests that p38α is the “dominant” form but that functional redundancy exists between the two related protein kinase. p38β has been shown to play specific roles in gene expression, regulation of cell death, cell differentiation and neuropathic pain. However, p38β is not involved in transducing pro-inflammatory signals, myogenesis or cell motility, when p38α is present.

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Mannose/mannan-binding lectin

Mannose/mannan-binding lectin (MBL) is a serum lectin synthesized (as a ~32 kDa peptide) by the liver and is one of the key molecules of the innate immune system. Each peptide has an N (amino)-terminal cysteine-rich region, a middle stretch of a collagen-like sequence, and a carbohydrate recognition domain (CRD) in the C (carboxy)-terminus. Three identical peptides form a structural subunit, similar to a collagenous triple helix, which is the basic building block of all circulating molecular forms of MBL. Further oligomerization of these structural subunits by disulphide bonds in the N-terminal region results in MBL molecules of different sizes (from dimers to hexamers), but the hexameric form is probably the most common. MBL-associated serine proteases (MASPs) bind to MBL multimeric forms to stabilize the molecule. MBL is a pattern-recognition receptor and the CRDs of MBL serve to bind to a wide range of pathogens such as bacteria, viruses and protozoa, by recognizing carbohydrate moieties on their surfaces. There are two pathways by which MBL can participate in a host defense response: 1) MBL activates the lectin complement pathway via MASPs, that converges with the classical complement pathway, at the level of complement C4 (C4-A or C4-B), and 2) MBL may also act directly as an opsonin, enhancing phagocytosis by binding to cell-surface receptors present on phagocytic cells.

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Leukocyte surface antigen CD47

CD47, also known as integrin-associated protein (IAP), ovarian cancer antigen OA3, Rh-related antigen and MER6, is a widely expressed transmembrane receptor belonging to the immunoglobulin superfamily. CD47 is the counter-receptor for two members of the signal-regulatory protein (SHPS/SIRP) family and a high-affinity receptor for the secreted protein thrombospondin-1. Interactions with SIRP receptors play roles in self recognition and regulation of innate immune responses. Over-expression of CD47 on some cancers is a negative prognostic factor and protects against innate immune surveillance. Engagement of CD47 on vascular cells by thrombospondin-1 regulates calcium, cAMP, and nitric oxide/cGMP signaling pathways that control blood pressure, tissue perfusion, and angiogenesis. Moreover, CD47 signaling in various cell types regulates pathways that can trigger cell death, limit stem cell self-renewal, regulate mitochondrial homeostasis and other differentiation pathways, and activate protective autophagy responses under tissue stress. On red blood cells CD47 is part of the Rh complex, but on other cell types it associates laterally in the membrane with integrins and specific signaling receptors. Impaired responses to cardiovascular stress and some pathogens in mice lacking CD47 and their enhanced survival of fixed ischemia, ischemia/reperfusion and radiation injuries identify important pathophysiological roles for CD47 in inflammatory responses and adaptation to stress.

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L-ficolin is a serum lectin synthesized (as a ~37 kDa polypeptide) predominantly by the liver, and is one of the key molecules of the innate immune system. It has an amino (N)-terminal cysteine-rich region, a middle stretch of a collagen-like sequence, and a fibrinogen-like domain in the carboxy (C)-terminus. Three identical polypeptides form a structural (triple helical) subunit, with the help of the collagen-like domain. Further oligomerization of this subunit results in different sized L-ficolin molecules (from dimers to tetramers) in circulation. However, the tetrameric form (composed of 12 polypeptides) is the most prevalent structure. The polypeptides in the structural subunit are cross-linked by disulphide bonds in the N-terminal region. The fibrinogen-like domain forms a globular structure. The overall structure of oligomeric L-ficolin closely resembles mannose-binding lectin (MBL). Similar to MBL, L-ficolin also acts as a pattern recognition receptor. It primarily recognizes acetylated sugar residues on the cell surface of different gram-positive and gram-negative bacteria, viruses and other pathogens. There are two pathways by which L-ficolin may participate in a host defense response: 1) It activates the complement lectin pathway, via MBL/ficolin associated serine proteases (MASPs), that converges with the classical complement pathway at the level of complement C4, and 2) it may also act directly as an opsonin, enhancing phagocytosis by binding to cell-surface receptors present on phagocytic cells. M-ficolin and H-ficolin are structurally similar to L-ficolin. However, they differ in their tissue expression and binding affinities to pathogenic ligands.

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Tsh receptor

The TSH receptor is a member of the G protein-coupled receptor(GPCR)family. It is one of the glycoprotein hormone receptors, which also includes the FSH and LH/CG receptors. The TSH receptor mediates the action of the pituitary-derived glycoprotein, TSH (thyroid stimulating hormone, thyrotropin or thyrotrophin). TSH binds to the TSH receptor which is located on thyroid follicular cells (but is also expressed in extrathyroidal sites). Glycosylation of the TSH receptor occurs, as does cleavage of the receptor from an intact to an extracellular form (α subunit), which may be shed after deletion of a short region (aa 316-366) near the C terminal of the extracellular domain, thus leaving a transmembrane form (β subunit). The α subunit is responsible for ligand/autoantibody binding, facilitated by glycosylation and possibly by the extracellular loops of the 7 transmembrane segments. The intracellular loops of the β subunit interact with G proteins when the receptor is activated. The receptor may also exist in multimeric forms, although it is not clear whether these forms play a role in TSH receptor function. TSH action involves cAMP and IP/DAG responses. The TSH receptor controls positively both the function (production of thyroid hormones T3 and T4) and growth of the thyroid.

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