title: Functional requirement of tyrosine residue 429 within CD5 cytoplasmic domain for regulation of T cell activation and survival.
abstract: CD5 has been mainly described as a negative regulator of TCR and BCR signaling and recent evidence has shown an important role for this receptor in delivering pro-survival signals. However, the molecular mechanisms underlying these processes remain unresolved. TCR crosslinking leads to phosphorylation of three tyrosine residues within the cytoplasmic tail of CD5 (Y429, Y441 and Y463) leading to the recruitment of signaling molecules like PI3K, c-Cbl and RasGAP; nevertheless, the role of these residues in T cell survival has not yet been assessed. In this study, we show that alanine-scanning mutagenesis of such tyrosine residues, either singly or in combination, leads to an increased thymocyte cell death with or without α-CD3 stimulation. Remarkably, the T-cell death observed with each individual tyrosine mutant was Caspase 3-independent. Furthermore, Y429 mutation resulted in a hyper-phosphorylation of ERK suggesting that this tyrosine residue regulates cell survival through down modulation of TCR signaling. Mutation of Y441 or Y463 did not induce hyper-responsiveness to TCR activation, indicating that they promoted T-cell survival by a TCR signal-independent pathway. Our results show that three tyrosine-based domains within CD5 cytoplasmic tail promote T-cell survival through non-overlapping mechanisms. This study also reveals that Y429 domain of CD5, previously described as a "pseudo ITAM", is functionally an ITIM domain in T cells.
authors.affiliation: Departamento de Inmunología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, México, DF 04510, Mexico.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Mier-Aguilar
authors.affiliation: Departamento de Inmunología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, México, DF 04510, Mexico.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Vega-Baray
authors.affiliation: Departamento de Inmunología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, México, DF 04510, Mexico.
authors.forename: Erica
authors.initials: E
authors.lastname: Burgueño-Bucio
authors.affiliation: Servei d'Immunologia, Hospital Clinic i Provincial de Barcelona, Institut d'Investigaciones Biomédiques August Pi i Sunyer (IDIBABS), Departament de Biologia Cel.lular, Immunologia i Neurociències, Universitat de Barcelona, Barcelona 08036, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Lozano
authors.affiliation: Departamento de Inmunología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, México, DF 04510, Mexico.
authors.forename: Eduardo A
authors.initials: EA
authors.lastname: García-Zepeda
authors.affiliation: Division of Clinical Immunology and Rheumatology, Departments of Medicine, and Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Chander
authors.initials: C
authors.lastname: Raman
authors.affiliation: Departamento de Inmunología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, México, DF 04510, Mexico. Electronic address: soldevi@unam.mx.
authors.forename: Gloria
authors.initials: G
authors.lastname: Soldevila
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D017304:Annexin A5 / Q000737:chemistry; D018956:CD5 Antigens / Q000737:chemistry*; D053148:Caspase 3 / Q000378:metabolism; D002470:Cell Survival; D003593:Cytoplasm / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D008213:Lymphocyte Activation; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology; D060168:Thymocytes / Q000166:cytology; D014443:Tyrosine / Q000737:chemistry*
chemical_list: D017304:Annexin A5; D018956:CD5 Antigens; D011948:Receptors, Antigen, T-Cell; D014443:Tyrosine; D053148:Caspase 3
keywords: Apoptosis; CD5; Phosphorylation; Signaling; TCR; Tyrosines