title: ShcA regulates thymocyte proliferation through specific transcription factors and a c-Abl-dependent signaling axis.
abstract: Signaling via the pre-T-cell receptor (pre-TCR), along with associated signals from Notch and chemokine receptors, regulates the β-selection checkpoint that operates on CD4(-) CD8(-) doubly negative (DN) thymocytes. Since many hematopoietic malignancies arise at the immature developmental stages of lymphocytes, understanding the signal integration and how specific signaling molecules and distal transcription factors regulate cellular outcomes is of importance. Here, a series of molecular and genetic approaches revealed that the ShcA adapter protein critically influences proliferation and differentiation during β-selection. We found that ShcA functions downstream of the pre-TCR and p56(Lck) and show that ShcA is important for extracellular signal-regulated kinase (ERK)-dependent upregulation of transcription factors early growth factor 1 (Egr1) and Egr3 in immature thymocytes and, in turn, of the expression and function of the Id3 and E2A helix-loop-helix (HLH) proteins. ShcA also contributes to pre-TCR-mediated induction of c-Myc and additional cell cycle regulators. Moreover, using an unbiased Saccharomyces cerevisiae (yeast) screen, we identified c-Abl as a binding partner of phosphorylated ShcA and demonstrated the relevance of the ShcA-c-Abl interaction in immature thymocytes. Collectively, these data identify multiple modes by which ShcA can fine-tune the development of early thymocytes, including a previously unappreciated ShcA-c-Abl axis that regulates thymocyte proliferation.
authors.affiliation: Department of Microbiology, Immunology and Cancer Biology and Center for Cell Clearance, University of Virginia Health System, Charlottesville, Virginia, USA.
authors.forename: Paul C
authors.initials: PC
authors.lastname: Trampont
authors.affiliation: Department of Microbiology, Immunology and Cancer Biology and Center for Cell Clearance, University of Virginia Health System, Charlottesville, Virginia, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Microbiology, Immunology and Cancer Biology and Center for Cell Clearance, University of Virginia Health System, Charlottesville, Virginia, USA.
authors.forename: Amber J
authors.initials: AJ
authors.lastname: Giles
authors.affiliation: Department of Microbiology, Immunology and Cancer Biology and Center for Cell Clearance, University of Virginia Health System, Charlottesville, Virginia, USA.
authors.forename: Scott F
authors.initials: SF
authors.lastname: Walk
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Jing J
authors.initials: JJ
authors.lastname: Gu
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Ann Marie
authors.initials: AM
authors.lastname: Pendergast
authors.affiliation: Department of Microbiology, Immunology and Cancer Biology and Center for Cell Clearance, University of Virginia Health System, Charlottesville, Virginia, USA Ravi@virginia.edu.
authors.forename: Kodi S
authors.initials: KS
authors.lastname: Ravichandran
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism; D051776:Early Growth Response Protein 3 / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D051796:Inhibitor of Differentiation Proteins / Q000235:genetics; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008810:Mice, Inbred C57BL; D009154:Mutation; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D055765:Shc Signaling Adaptor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D060168:Thymocytes / Q000166:cytology* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; C497369:Egr3 protein, mouse; D051796:Inhibitor of Differentiation Proteins; D016271:Proto-Oncogene Proteins c-myc; D011948:Receptors, Antigen, T-Cell; D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D014157:Transcription Factors; C067679:Idb3 protein, mouse; D051776:Early Growth Response Protein 3; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D016315:Proto-Oncogene Proteins c-abl