IntroductionThe Bcl-2 protein contributes to the pathophysiology of cancer and the resistance of cancer to therapeutic agents by virtue of its ability to inhibit apoptosis. 1,2 The Bcl-2-positive lymphoid malignancies follicular lymphoma and chronic lymphocytic leukemia (CLL) are prime examples. They are associated with an elevation of Bcl-2 because of the t(14;18) chromosomal translocation in follicular lymphoma 3 and the loss of miR-15a and miR16-1 in CLL. 4,5 Cure of these malignancies is infrequently achieved with current therapeutic modalities, and thus a major challenge remains to develop new treatment modalities based on an understanding of the fundamental disease mechanisms. 6 Bcl-2 blocks apoptosis in part by binding its proapoptotic relatives, thus preserving mitochondrial integrity and preventing cytochrome c release. 7,8 Therefore, considerable investment has been made in the development of novel therapeutic agents, such as , that disrupt the inhibitory interaction of Bcl-2 with its proapoptotic relatives. 1,2,9-11 Several of these agents are currently undergoing clinical testing. However, Bcl-2 also inhibits apoptosis by regulating the release of Ca 2ϩ from the endoplasmic reticulum (ER). [12][13][14] This recently characterized mechanism involves a physical interaction of Bcl-2 with the inositol 1,4,5-trisphosphate receptor (IP 3 R) Ca 2ϩ -release channel on the ER. Through this interaction, Bcl-2 prevents cytoplasmic Ca 2ϩ elevation sufficient to trigger apoptosis. However, the potential contribution of the Bcl-2-IP 3 R interaction to the survival of CLL has not been investigated, so the opportunity for targeting this interaction therapeutically has not yet been realized.The IP 3 R is an IP 3 -gated Ca 2ϩ channel that is highly conserved, represented by 3 isoforms, and present in virtually all cell types. 15,16 IP 3 -dependent release of Ca 2ϩ from the ER into the cytoplasm produces Ca 2ϩ signals, generally in the form of Ca 2ϩ oscillations, which govern diverse cellular functions including cell proliferation and survival. 17,18 Ca 2ϩ oscillations support cell survival in part by positively regulating mitochondrial metabolism, but sustained high-amplitude elevations of Ca 2ϩ induce mitochondrial Ca 2ϩ overload and apoptosis. [19][20][21] Bcl-2 inhibits high-amplitude, proapoptotic Ca 2ϩ elevation but does not interfere with physiologic Ca 2ϩ oscillations. 22 In fact, under certain circumstances Bcl-2 and its homolog Bcl-xl enhance Ca 2ϩ oscillations, [22][23][24][25][26] and through this mechanism are predicted to promote efficient mitochondrial bioenergetics. 27 Thus, Bcl-2 supports cell survival both by enhancing physiologic Ca 2ϩ signals and by blocking proapoptotic Ca 2ϩ elevation.A major focus of our work has been to understand how Bcl-2 inhibits proapoptotic elevation of Ca 2ϩ based on evidence that Bcl-2 binds to the IP 3 R and thus inhibits ER Ca 2ϩ release. [28][29][30][31][32] Although this interaction has been mainly detected in cell extracts by coimmunoprecipitation or blue native gel ...

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The dynamic and stringent coordination of kinase and phosphatase activity controls a myriad of physiologic processes. Aberrations that disrupt the balance of this interplay represent the basis of numerous diseases. For a variety of reasons, early work in this area portrayed kinases as the dominant actors in these signaling events with phosphatases playing a secondary role. In oncology, these efforts led to breakthroughs that have dramatically altered the course of certain diseases and directed vast resources toward the development of additional kinase-targeted therapies. Yet, more recent scientific efforts have demonstrated a prominent and sometimes driving role for phosphatases across numerous malignancies. This maturation of the phosphatase field has brought with it the promise of further therapeutic advances in the field of oncology. In this review, we discuss the role of phosphatases in the regulation of cellular proliferation and survival signaling using the examples of the MAPK and PI3K/AKT pathways, c-Myc and the apoptosis machinery. Emphasis is placed on instances where these signaling networks are perturbed by dysregulation of specific phosphatases to favor growth and persistence of human cancer.