Targeted activation of the SHP-1/PP2A signaling axis elicits apoptosis of chronic lymphocytic leukemia cells

Abstract

Lyn, a member of the Src family of kinases, is a key factor in the dysregulation of survival and apoptotic pathways of malignant B cells in chronic lymphocytic leukemia. One of the effects of Lyn’s action is spatial and functional segregation of the tyrosine phosphatase SHP-1 into two pools, one beneath the plasma membrane in an active state promoting pro-survival signals, the other in the cytosol in an inhibited conformation and unable to counter the elevated level of cytosolic tyrosine phosphorylation. We herein show that SHP-1 activity can be elicited directly by nintedanib, an agent also known as a triple angiokinase inhibitor, circumventing the phospho-S591-dependent inhibition of the phosphatase, leading to the dephosphorylation of pro-apoptotic players such as procaspase-8 and serine/threonine phosphatase 2A, eventually triggering apoptosis. Furthermore, the activation of PP2A by using MP07-66, a novel FTY720 analog, stimulated SHP-1 activity via dephosphorylation of phospho-S591, which unveiled the existence of a positive feedback signaling loop involving the two phosphatases. In addition to providing further insights into the molecular basis of this disease, our findings indicate that the PP2A/SHP-1 axis may emerge as an attractive, novel target for the development of alternative strategies in the treatment of chronic lymphocytic leukemia.

Rules for PP2A-controlled phosphosignalling and drug responses

“…Especially interesting is the evidence that inhibition of protein dephosphorylation is an integral part of chromatin-associated functions of nuclear PP2A inhibitor protein SET. Together with previous data indicating strong association of SET with histones, we speculate that this may generate spatially restricted inhibition of dephosphorylation of chromatin remodeling complexes and that SET modulation by emerging small molecule approaches 70 , may provide novel opportunities for targeting epigenetic gene regulation.…”

Targeted therapies don't work for a reason; the neglected tumor suppressor phosphatase PP2A strikes back

“…Currently, partial crystal structures of CIP2A, PME-1, and SET are known [40][41][42], and there is already relatively good understanding of how each of these PIPs modulate PP2A activity [30,40,43]. Small-molecule SET inhibitors have already been identified, and they have shown promise in inhibiting oncogenic signaling and malignant cell behavior [21,32,[44][45][46]. In accordance with the major theme of this review, a recent study demonstrated that combination of SET targeting and tyrosine kinase inhibitor provides an effective therapeutic approach in human T-cell acute lymphoblastic leukemia [34].…”

Oxidation Impacts the Intracellular Signaling Machinery in Hematological Disorders

“…On the other hand, SHP-1 exists in CLL cells as two distinct pools, one of which is bound to the Tyr-phosphorylated cytoplasmic tail of the transmembrane CLL marker CD5, most likely supporting pro-survival pathways, and the other that is located in the cytoplasm in an inactive form that can be reactivated by small molecules that disrupt the inhibitory intramolecular interactions. Importantly, the restoration of the activity of these two phosphatases has been reported to evoke CLL cell apoptosis by disrupting the phosphorylation-dependent pro-survival and antiapoptotic signaling network [13,62]. In this regard, we recently showed that compounds restoring the activity of PP2A and SHP-1, which is largely impaired in varied types of cancer, constrained kinase-orchestrated survival signaling pathways, thereby inducing apoptosis in CLL cells; notably, the use of such activators in combination with kinase inhibitors resulted in a dramatic synergistic effect [12,63], which may open a new avenue in the development of new therapeutic strategies.…”

“…Furthermore, oxidation might directly induce/modulate kinase activity such as in Src family kinases (SFKs) or Akt serine-threonine kinase [6][7][8][9][10][11]. Translational studies have revealed the important link between oxidation and signal transduction pathways in both oncologic and benign hematological disorders [12][13][14][15][16][17][18][19][20][21]. In this review, we focus on models of globally distributed hematological diseases for which the link between intracellular signaling and oxidation has been recently reported.…”