T cell activation is a critical step in the development of a proper immune response to infection and inflammation. This dynamic process requires efficient T cell receptor signaling, which in turn is modulated by integrin receptor activation and the actin cytoskeleton. CD45 is a key player in T cell receptor mediated signal transduction. However, its exact role in integrin mediated signaling in T cells remains to be elucidated. The present study addresses the relationship between CD45 and beta1-integrin mediated survival signaling in the human T leukemic cell line Jurkat, in which collagen receptors alpha1 beta1 and alpha2 beta1 integrins are localized. Wild type (WT)-Jurkat T cells treated with collagen demonstrated increased cell proliferation and survival. Monitoring the intracellular signaling pathways activated by collagen in WT-Jurkat cells revealed increased focal adhesion kinase (FAK) and extracellular signal-regulated kinase (ERK) activation. Moreover, examination of the actin cytoskeleton of WT-Jurkat T cells treated with collagen demonstrated the presence of an organized cortical actin structure, reminiscent of the survival phenotype. This is in contrast to CD45-deficient J45.01 T cells, where collagen treatment failed to enhance cell proliferation/survival and was unable to stimulate FAK and ERK activity. In addition, the actin cytoskeleton of collagen treated J45.01 T cells was disorganized with cortical actin aggregates present throughout. The importance of an organized actin cytoskeleton to proper cell signaling and survival was further demonstrated by the inability of collagen treated WT-Jurkat cells to activate the FAK and ERK survival pathway in the presence of cytochalasin D, a cytoskeleton-disrupting drug. Consistently, addition of the CD45 specific inhibitor abolished collagen-stimulated FAK and ERK activation in WT-Jurkat cells, further depicting CD45 as the key mediator. Furthermore, collagen-mediated T cell signaling alone was able to activate IL-2 gene transcription devoid of concomitant T cell receptor activation. Taken together, these results are the first to demonstrate that CD45 is important in promoting cell survival by modulating integrin-mediated FAK/ERK signaling in Jurkat T cells and is involved in a distinct signal transduction pathway, separate from T cell receptor signaling, influencing T cell immune responses. Hence, this study will help further our knowledge about beta1-integrin mediated signaling in T cells, which may prove to be essential for the regulation of various T cell mediated immune responses.