Genetics of dark skin in mice

Fitch, Karen R.; McGowan, Kelly A.; Raamsdonk, Catherine D. Van; Fuchs, Helmut; Lee, Daekee; Puech, Anne; Hérault, Yann; Threadgill, David W.; Angelis, Martin Hrabé de; Barsh, Gregory S.

doi:10.1101/gad.1023703

Cited by 128 publications

(147 citation statements)

References 63 publications

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“…Autophosphorylation of the activation loop in protein kinase A, insulin receptor tyrosine kinase, and Src yields a 5-to 500-fold increase in kinase activity (23,24). Mutations of other residues in the EGFR activation loop, such as the L858R mutation seen in human lung cancer and the mouse gain-of-function mutation L861Q, have dramatic effects on kinase activity, downstream signaling, and small-molecule inhibitor sensitivity (31)(32)(33). Although a role for activation loop phosphorylation in EGFR and Her2 has been controversial (34-37), our demonstration of Her2 Y877 phosphorylation warrants renewed interest in this site.…”

Section: Discussionmentioning

confidence: 99%

Phosphoproteomic analysis of Her2/neu signaling and inhibition

Bose¹,

Molina²,

Patterson³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

191

173

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Her2͞neu (Her2) is a tyrosine kinase belonging to the EGF receptor (EGFR)͞ErbB family and is overexpressed in 20 -30% of human breast cancers. We sought to characterize Her2 signal transduction pathways further by using MS-based quantitative proteomics. Stably transfected cell lines overexpressing Her2 or empty vector were generated, and the effect of an EGFR and Her2 selective tyrosine kinase inhibitor, PD168393, on these cells was characterized. Quantitative measurements were obtained on 462 proteins by using the SILAC (stable isotope labeling with amino acids in cell culture) method to monitor three conditions simultaneously. Of these proteins, 198 showed a significant increase in tyrosine phosphorylation in Her2-overexpressing cells, and 81 showed a significant decrease in phosphorylation. Treatment of Her2-overexpressing cells with PD168393 showed rapid reversibility of the majority of the Her2-triggered phosphorylation events. Phosphoproteins that were identified included many known Her2 signaling molecules as well as known EGFR signaling proteins that had not been previously linked to Her2, such as Stat1, Dok1, and ␦-catenin. Importantly, several previously uncharacterized Her2 signaling proteins were identified, including Axl tyrosine kinase, the adaptor protein Fyb, and the calcium-binding protein Pdcd-6͞Alg-2. We also identified a phosphorylation site in Her2, Y877, which is located in the activation loop of the kinase domain, is distinct from the known C-terminal tail autophosphorylation sites, and may have important implications for regulation of Her2 signaling. Network modeling, which combined phosphoproteomic results with literature-curated protein-protein interaction data, was used to suggest roles for some of the previously unidentified Her2 signaling proteins.breast cancer ͉ cellular networks ͉ proteomics ͉ signal transduction ͉ tyrosine kinase inhibitors

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Section: Discussionmentioning

confidence: 99%

Phosphoproteomic analysis of Her2/neu signaling and inhibition

Bose¹,

Molina²,

Patterson³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

191

173

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“…3), although other pathways clearly exist (Barsh 1996;Fitch et al 2003;Van Raamsdonk et al 2004;Lamason et al 2005), and will likely provide valuable insights to the pigmentation process. MSH binds to its receptor, Mc1R, in a manner that is directly competed by the agouti protein in nonhuman mammalian species (the role of agouti in man is less clear).…”

Section: Msh Signalingmentioning

confidence: 99%

Malignant melanoma: genetics and therapeutics in the genomic era

2006

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Cell for cell, probably no human cancer is as aggressive as melanoma. It is among a handful of cancers whose dimensions are reported in millimeters. Tumor thickness approaching 4 mm presents a high risk of metastasis, and a diagnosis of metastatic melanoma carries with it an abysmal median survival of 6-9 mo. What features of this malignancy account for such aggressive behavior? Is it the migratory history of its cell of origin or the programmed adaptation of its differentiated progeny to environmental stress, particularly ultraviolet radiation? While the answers to these questions are far from complete, major strides have been made in our understanding of the cellular, molecular, and genetic underpinnings of melanoma. More importantly, these discoveries carry profound implications for the development of therapies focused directly at the molecular engines driving melanoma, suggesting that we may have reached the brink of an unprecedented opportunity to translate basic science into clinical advances. In this review, we attempt to summarize our current understanding of the genetics and biology of this disease, drawing from expanding genomic information and lessons from development and genetically engineered mouse models. In addition, we look forward toward how these new insights will impact on therapeutic options for metastatic melanoma in the near future. The diseaseMelanomas most often arise within epidermal melanocytes of the skin, although they can also derive from noncutaneous melanocytes such as those lining the choroidal layer of the eye, GI and GU mucosal surfaces, or the meninges. Melanoma is also among the more common causes of "metastatic cancer of unknown primary," which may reflect either a propensity to arise in unexpected sites along the neural crest migratory route, or rapid growth of poorly differentiated lesions arising from indolent or unrecognized cutaneous primary lesions. Clinical staging for primary cutaneous melanoma employs measurements of thickness (in millimeters), presence of ulceration, penetration through cutaneous layers, mitotic rate, evidence of "in transit" metastasis, tumor spread to draining lymph nodes, and evidence of distant metastasis. Management issues in melanoma can be classified in terms of prevention, diagnosis, local disease management, and treatment of metastatic disease.In view of the epidemiological and emerging experimental evidence linking melanoma incidence to UV exposure and skin phototype, prevention and screening strategies represent key areas for reduction of disease incidence and severity. For most cutaneous melanomas in the so-called radial growth phase (e.g., thin melanomas), surgical removal affords curative treatment. In contrast, a significant fraction of patients diagnosed with intermediate-thickness (2-4 mm) cutaneous melanoma eventually succumb to recurrence at regional or distant sites.Critical biological questions facing the melanoma research community include: (1) What genetic and environmental factors contribute to and/or modulate risk of melanom...

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“…Until recently, few mouse models were available for studying the genetics of skin color. Large-scale mutagenesis screens, however, have now identified a large class of dark skin pigment mutations that has resulted in novel insights into skin color in mice (Fitch et al, 2003;Van Raamsdonk et al, 2004). These mutations increase either dermal or epidermal pigmentation (Fitch et al, 2003).…”

Section: Dark Skin Mutationsmentioning

confidence: 99%

“…Large-scale mutagenesis screens, however, have now identified a large class of dark skin pigment mutations that has resulted in novel insights into skin color in mice (Fitch et al, 2003;Van Raamsdonk et al, 2004). These mutations increase either dermal or epidermal pigmentation (Fitch et al, 2003). Three of the four in the dermal class of Dark skin mutations (two different complementation groups, namely Dsk1 and Dsk7) affect the Gnaq and Gna11 genes, which encode two related G␣ subunits, proteins that mediate the signal from G-protein coupled receptors (Van Raamsdonk et al, 2004).…”

Section: Dark Skin Mutationsmentioning

confidence: 99%

Mouse coat color mutations: From fancy mice to functional genomics

Steingrı́msson

Copeland

Jenkins

2006

Developmental Dynamics

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Mouse coat color mutations have a long history in biomedical research. The viable and visible phenotype of most coat color mutations has made the pigment cell, the melanocyte, an ideal system for genetic, molecular, and cellular analysis. Molecular cloning and analysis of many of the different coat color mutations have revealed the roles of a diverse range of genes, and today we know more about the pathways and proteins that regulate the development and function of pigment cells than we know about most other cell types in mammalian organisms. Coat color mutations have also provided novel insights into stem cell biology and human diseases, including melanoma. In the future, it will be important to build on this history and knowledge by taking advantage of the extensive repertoire of recently developed genome-wide methodologies, available genomic information, and the powerful methods that have been developed for modifying the mouse genome to systematically dissect the development and function of this important cell type. The usefulness of coat color mutations has just begun to emerge. Developmental Dynamics 235: 2401-2411, 2006.

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Genetics of dark skin in mice

Cited by 128 publications

References 63 publications

Phosphoproteomic analysis of Her2/neu signaling and inhibition

Phosphoproteomic analysis of Her2/neu signaling and inhibition

Malignant melanoma: genetics and therapeutics in the genomic era

Mouse coat color mutations: From fancy mice to functional genomics

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