Serine/threonine phosphorylation in cytokine signal transduction

Over the past decade, the involvement of tyrosine kinases in signal transdu ction pathways evoked by cytokines has been intensively investigated. Only relatively recently have the roles of serine/threonine kinases in cytokine- induced signal transduction and anti-apoptotic pathways been examined. Cyto kine receptors without intrinsic kinase activity such as interleukin-3 (IL- 3), granulocyte-macrophage colony-stimulating factor (GM-CSF) and the inter ferons were thought to transmit their regulatory signals primarily by the r eceptor-associated Jak family of tyrosine kinases. This family of tyrosine kinases activates STAT transcription factors, which subsequently transduced their signals into the nucleus to modulate gene expression. Cytokine recep tors with intrinsic tyrosine kinase activity such as c-Kit were initially t hought to transduce their signals independently of serine/threonine kinase cascades. Recently, both of these types of receptor signaling pathways have been shown to interact with serine/threonine kinase pathways as maximal ac tivation of these tyrosine kinase regulated cascades involve serine/threonl ne phosphorylation modulated by, for example MAP kinases. A common intermed iate pathway initiating from cytokine receptors is the Ras/Raf/MEK/ERK (MAP K) cascade, which can result in the phosphorylation and activation of addit ional downstream kinases and transcription factors such as p90(Rsk), ORES, Elk and Egr-1. Serine/threonine phosphorylation is also involved in the reg ulation of the apoptosis-controlling Bcl-2 protein, as certain phosphorylat ion events induced by cytokines such as IL-3 are anti-apoptotic, whereas ot her phosphorylation events triggered by chemotherapeutic drugs such as Pacl itaxel are associated with cell death. Serine/threonine phosphorylation is implicated in the etiology of certain human cancers as constitutive serine phosphorylation of STATs 1 and 3 is observed in chronic lymphocytic leukemi a and can be inhibited by the chemotherapeutic drug fludarabine, Serine/thr eonine phosphorylation also plays a role in the etiology of immunodeficienc ies. Activated STAT5 proteins are detected in reduced levels in lymphocytes recovered from HIV-infected individuals and immunocompromised mice. Serine /threonine phosphorylation may be an important target of certain chemothera peutic drugs which recognize the activated proteins. This meeting report an d mini-review will discuss the interactions of serine/threonine kinases wit h signal transduction and apoptotic molecules and how some of these pathway s can be controlled by chemotherapeutic drugs.