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

[waldenstrÃ¶m macroglobulinemia]

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 serine 17 . P-7 hyperphosphorylation can be induced in wild-type P-7 (wtP-7 ) carriers by PKC Î¶ and reverted by protein-phosphatase 2 A (PP 2 A ). Here we show that dephosphorylation of pP-7 is defective in pP-7 carriers due to inactivation of the PP 2 A by substitution of the regulatory B 55 Î´ subunit with B 56 Î³ 3 . In lymphoblastoid cell lines from pP-7 carriers , transfection of recombinant B 55 Î´ or treatment with ceramide led to a partial reconstitution of PP 2 A activity and dephosphorylation of pP-7 to wtP 7 . 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 .

Diseases
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Diseases presenting "partial reconstitution" symptom

waldenstrÃ¶m macroglobulinemia

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