Signal Transducer and Activator of Transcription-3 (STAT3) Is Constitutively Activated in Normal, Self-renewing B-1 Cells but Only Inducibly Expressed in Conventional B Lymphocytes

Abstract

Cytokine and growth factor receptor engagement leads to the rapid phosphorylation and activation of latent, cytosolic signal transducers and activators of transcription (STAT) proteins, which then translocate to the nucleus where they regulate transcriptional events from specific promoter sequences. STAT3 expression in particular has been associated with Abl, Src, and HTLV-1 transformation of normal cells. B-1 lymphocytes are self-renewing, CD5+ B cells that display a propensity for malignant transformation and are the normal counterpart to human chronic lymphocytic leukemias. Further, B-1 cells are characterized by aberrant intracellular signaling, including hyperresponsiveness to phorbol ester PKC agonists. Here we demonstrate that B-1 lymphocytes constitutively express nuclear activated STAT3, which is not expressed by unmanipulated conventional (B-2) lymphocytes. In contrast, STAT3 activation is induced in B-2 cells after antigen receptor engagement in a delayed fashion (after 3 h). Induction of STAT3 is inhibited by both the serine/threonine protein kinase inhibitor H-7 and the immunosuppressive drug rapamycin and requires de novo protein synthesis, demonstrating novel coupling between sIg and STAT proteins that differs from the classical paradigm for STAT induction by cytokine receptors. The inability of prolonged stimulation of conventional B-2 cells with anti-Ig, a treatment sufficient to induce CD5 expression, to result in sustained STAT3 activation suggests that STAT3 is a specific nuclear marker for B-1 cells. Thus, STAT3 may play a role in B cell antigen-specific signaling responses, and its constitutive activation is associated with a normal cell population exhibiting intrinsic proliferative behavior.

The SRC family kinase LYN redirects B cell receptor signaling in human SLP65-deficient B cell lymphoma cells

“…In normal B cells, B cell receptor engagement results in activation of STAT5 (Karras et al, 1996) and mitogen activated protein kinases (MAPK; Richards et al, 2001), which induce survival and proliferation, respectively. Likewise, B cell receptor engagement induced tyrosine phosphorylation of STAT5 and MAPK1 in two SLP65-deficient and one SLP65-expressing B cell lymphoma cell lines (Figure 4).…”

The biology of Stat4 and Stat6

“…In primary B lymphocytes both Ig and CD40 crosslinking can induce Stat6 tyrosine phosphorylation (Karras et al, 1996(Karras et al, , 1997. In the case of Ig crosslinking, there appears to be an additional dependence on PKC to mediate this signal (Karras et al, 1996).…”

Serine/threonine phosphorylation in cytokine signal transduction

“…The development of a powerful series of antibodies which specifically recognize the activated STAT proteins has allowed Dr Frank to demonstrate that in chronic lymphocytic leukemia (CLL), the most common form of leukemia in the United States, there is constitive phosphorylation of the STAT1 and STAT3 proteins on serine-727. [93][94][95][96][97][98][99] In contrast, MAPK (ERK1 and ERK2) are not constitutively activated in these CLL patients. These observations have clinical significance since treatment of CLL patients with fludarabine, leads to a specific loss of STAT1.…”