title: CD25 and CD69 induction by α4β1 outside-in signalling requires TCR early signalling complex proteins.
abstract: Distinct signalling pathways producing diverse cellular outcomes can utilize similar subsets of proteins. For example, proteins from the TCR (T-cell receptor) ESC (early signalling complex) are also involved in interferon-α receptor signalling. Defining the mechanism for how these proteins function within a given pathway is important in understanding the integration and communication of signalling networks with one another. We investigated the contributions of the TCR ESC proteins Lck (lymphocyte-specific kinase), ZAP-70 (ζ-chain-associated protein of 70 kDa), Vav1, SLP-76 [SH2 (Src homology 2)-domain-containing leukocyte protein of 76 kDa] and LAT (linker for activation of T-cells) to integrin outside-in signalling in human T-cells. Lck, ZAP-70, SLP-76, Vav1 and LAT were activated by α4β1 outside-in signalling, but in a manner different from TCR signalling. TCR stimulation recruits ESC proteins to activate the mitogen-activated protein kinase ERK (extracellular-signal-regulated kinase). α4β1 outside-in-mediated ERK activation did not require TCR ESC proteins. However, α4β1 outside-in signalling induced CD25 and co-stimulated CD69 and this was dependent on TCR ESC proteins. TCR and α4β1 outside-in signalling are integrated through the common use of TCR ESC proteins; however, these proteins display functionally distinct roles in these pathways. These novel insights into the cross-talk between integrin outside-in and TCR signalling pathways are highly relevant to the development of therapeutic strategies to overcome disease associated with T-cell deregulation.
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, U.S.A.
authors.forename: Ann-Marie
authors.initials: AM
authors.lastname: Cimo
authors.forename: Zamal
authors.initials: Z
authors.lastname: Ahmed
authors.forename: Bradley W
authors.initials: BW
authors.lastname: McIntyre
authors.forename: Dorothy E
authors.initials: DE
authors.lastname: Lewis
authors.forename: John E
authors.initials: JE
authors.lastname: Ladbury
mesh_terms: D015703:Antigens, CD / Q000096:biosynthesis*; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis*; D006801:Humans; D039041:Integrin alpha4beta1 / Q000502:physiology*; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis*; D019169:Jurkat Cells; D037181:Lectins, C-Type / Q000096:biosynthesis*; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D013997:Time Factors; D000099192:CD69 Antigens
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D039041:Integrin alpha4beta1; D053645:Interleukin-2 Receptor alpha Subunit; D037181:Lectins, C-Type; D011948:Receptors, Antigen, T-Cell; D000099192:CD69 Antigens; C508017:IL2RA protein, human