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Open Access Publications from the University of California


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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Inaugural issue of UCSD Molecule Pages

We are pleased to launch the inaugural issue of the

UCSD Molecule Pages






BARD1 was originally identified as a protein interacting with BRCA1, the breast cancer predisposition gene product. BARD1, like BRCA1, has an amino-terminal RING-finger domain and carboxy-terminal BRCT domains. In addition, BARD1 has three ankyrin repeats adjacent to the BRCT domains. BARD1 and BRCA1 form a stable heterodimer via their RING-finger domains. BRCA1, like many RING-finger proteins, has E3 ubiquitin ligase activity, which is amplified when in association with BARD1. By contrast, BARD1 alone has no such activity. The binding of BARD1 to BRCA1 stabilizes BRCA1 and, to some extent, BARD1. BARD1 and BRCA1 are co-expressed in most proliferating tissues and are localized to the nucleus. Based mostly on its ubiquitin ligase activity, the BARD1/BRCA1 complex has functions in DNA repair, transcriptional regulation, chromatin condensation, cell-cycle regulation, mitotic spindle formation and cytokinesis. BARD1 is highly conserved, having orthologs in many species. In mice, BARD1 has essential functions during development, and Bard1-null mice, like Brca1-null mice, die between embryonic days 7 and 8, suggesting that the defect is caused by the lack of a functional BARD1/BRCA1 heterodimer. Whereas only a few somatic and germline mutations of BARD1 have been found associated with breast, ovarian and endometrial cancer, nine commonly found alleles of BARD1 that contain single nucleotide polymorphisms have been found to be significantly associated with childhood neuroblastoma. In breast and ovarian cancers, truncated forms of BARD1 derived by differential RNA splicing are highly upregulated and are localized to the cytoplasm. The expression of these BARD1 isoforms in breast and ovarian cancer is correlated with a poor prognosis.

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NK1 (substance P) receptor

Neurokinin-1 receptor (NK1R), or substance P receptor, is a G protein-coupled receptor (GPCR) that transmits the signal of substance P (SP) and other tachykinins. Upon stimulation by its agonist SP, NK1R has been shown to interact with multiple G proteins, including Gs, Gq/11, Gi/o, G12, and G13. NK1R undergoes a rapid agonist-dependent desensitization, which is mediated by members of G protein receptor kinases (GRKs) and β-arrestins. NK1R is widely distributed in the central and peripheral nervous systems, as well as in the gastrointestinal tract, immune system, and skin. NK1R plays a key role in many physiological and pathophysiological processes, including pain, inflammation, cancer, brain edema, traumatic brain injury, nausea and vomiting, affective disorders, and obesity. Several pharmaceutical companies are actively developing compounds to target NK1R for its therapeutic potential. The first FDA approval for a NK1R antagonist was obtained in 2003 for aprepitant, which is indicated for chemotherapy-induced nausea and vomiting.

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Mammalian Numb (Numb) encodes an endocytic adaptor protein first characterized in the Drosophila nervous system as an intrinsic cell fate determinant which is asymmetrically localized and preferentially segregates into only one of the two daughter cells upon division (Rhyu et al. 1994; Knoblich et al. 1995; Spana and Doe 1995). Mammalian Numb homologues have been identified, and homozygous deletion of Numb in mice leads to embryonic lethality, suggesting that Numb plays an essential role in mammalian development (Verdi et al. 1996; Zhong et al. 1996). In addition to playing a role in asymmetric cell division(ACD), Numb has been shown to function in endocytosis, ubiquitination, cell adhesion, migration, and cancer.

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Phosphodiesterase 8A, cAMP-specific

Phosphodiesterase 8A (PDE8A) is a 3′,5′-cyclic-nucleotide phosphodiesterase that specifically catalyses the hydrolysis of cAMP to AMP. PDE8A is one of the two isoenzymes of the PDE8 family, the other being PDE8B. These two highly similar proteins have several common features that distinguish them from other cAMP-specific PDEs: they have very high affinity for the substrate cAMP; they are insensitive to the non-specific PDE inhibitor IBMX. They contain a PAS (Per, Arnt and Sim) and a REC (receiver) domain, both of which are observed in many signal transduction proteins. The possible function(s) of the PAS domain in PDE8 is still unknown. PDE8A mRNA is not expressed in all tissues but has been detected in several and is highest in testis, spleen, small intestine, heart, ovary, colon and kidney. Until early 2009, the lack of specific small-molecule inhibitors slowed the study of the physiological relevance of PDE8A; thus to date many aspects of this PDE's functions (that is, whether it is activated or regulated during certain cellular process) remain in large part unknown. So far, functions for PDE8A have been described in Leydig cells, where lack of PDE8A causes increased testosterone production in response to luteinizing hormone; T cells, where it seems to be induced during T cell activation and may control chemotaxis; and cardiocytes, where it seems to regulate calcium handling.

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The Smad Ubiquitination Regulatory Factor-1, or Smurf1, is an E3 ubiquitin ligase that catalyzes mono- or polyubiquitylation of protein targets which primarily function in TGFβ signaling pathways, but also include a growing list of substrates encompassing other molecular pathways and cellular processes distinct from TGFβ pathways. Smurf1 and a close homolog, Smurf2, are E3 ubiquitin ligases that belong to a small family of proteins distinguished by the presence of a catalytic, C-terminal region that is known as the HECT domain, for Homologous to E6AP C-Terminus. This region of the Smurfs and other HECT E3s form a covalent intermediate with ubiquitin (Ub) and subsequently transfer the Ub moiety to a substrate protein whose selection and targeting are governed by either direct interaction with Smurf1, or in concert with an adaptor protein(s) that bridges Smurf1 and the substrate. Smurf1 can operate throughout the cell and has a wide variety of protein targets, reflecting the diversity of biological processes it regulates, which spans cell proliferation, cell polarity, adhesion, apoptosis, differentiation, stem cell activity, embryonic development, pattern formation, organogenesis and organism physiology. Smurf1 is expressed in a wide range of cell types in developing embryos through adults, and Smurf1 gene orthologs are found in all lineages of the animal kingdom, from sponges through chordates. Defects in Smurf1 gene structure, expression or regulation are implicated in human diseases and birth defects, and Smurf1 is being actively pursued as a therapeutic target.

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