Inactivation of protein-phosphatase 2A causing hyperphosphorylation of autoantigenic paraprotein targets in MGUS/MM is due to an exchange of its regulatory subunits

Abstract

Hyperphosphorylated paratarg-7 (pP-7) carrier state is the strongest molecularly defined risk factor for monoclonal gammopathy of undetermined significance (MGUS), multiple myeloma (MM) and Waldenstrom's macroglobulinemia (WM). pP-7 is inherited as autosomal-dominant trait and depending on the ethnic background is found in over one-third of MGUS/MM patients. P-7, which is the antigenic paraprotein target in these patients, is hyperphosphorylated at serine17. P-7 hyperphosphorylation can be induced in wild-type P-7 (wtP-7) carriers by PKCζ and reverted by protein-phosphatase 2A (PP2A). Here we show that dephosphorylation of pP-7 is defective in pP-7 carriers due to inactivation of the PP2A by substitution of the regulatory B55δ subunit with B56γ3. In lymphoblastoid cell lines from pP-7 carriers, transfection of recombinant B55δ or treatment with ceramide led to a partial reconstitution of PP2A activity and dephosphorylation of pP-7 to wtP7. Similar results were observed with other previously reported autoantigenic paraproteins targets. In conclusion, the mechanisms responsible for the defective dephosphorylation and maintaining the hyperphosphorylated state of P-7 and other autoantigenic paraprotein targets have been elucidated, facilitating the identification of the genetic basis underlying this phenomenon which is obviously common in the pathogenesis of MGUS/MM/WM and not restricted to pP-7 cases. What's new? Paraproteins are abnormal antibodies. People who carry a mutation that alters a protein called 'paratarg-7' (for 'paraprotein target-7') have an increased risk for several cancers, including monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM). The altered form of paratarg-7 is hyperphosphorylated, due to loss of the enzyme protein-phosphatase 2A (PP2A). In this study, the authors identified the mechanism that inactivates PP2A. They also found that PP2A activity can be restored in vitro. This could eventually lead to a new therapeutic strategy for these cancers. © 2014 UICC.