Plasma Membrane Ca2+ATPase Isoform 4b Is Cleaved and Activated by Caspase-3 during the Early Phase of Apoptosis

Abstract

The plasma membrane Ca 2؉ pump (PMCA) is an essential element in the complex of mechanisms that maintain low intracellular Ca 2؉ concentration in the living cell. This pump is tightly regulated by calmodulin through binding to a high affinity calmodulin-binding domain at the C terminus that also serves as an autoinhibitor of the enzyme. Inspection of the C terminus of hPMCA4b, the most widely distributed form of PMCA, revealed a caspase-3 consensus sequence ( 1077 DEID 1080 ) just a few residues upstream of the calmodulin-binding domain. We demonstrate here that, in the early phase of apoptosis, hPMCA4b is cleaved at aspartic acid Asp 1080 mutants) were resistant to proteolysis. Based on these data, we conclude that hPMCA4b is a newly identified, natural caspase-3 substrate. We suggest that a constitutively active form of this protein, responding much faster to an increase in Ca 2؉ concentration than the autoinhibited form, may have an important role in regulating intracellular Ca 2؉ concentration in the apoptotic cell.

Isoform-specific up-regulation of plasma membrane Ca2+ATPase expression during colon and gastric cancer cell differentiation

“…Rather, a cross-talk exists between Ca 2+ signaling and various cellular signaling systems that control cell survival, proliferation, differentiation and apoptosis. An additional argument in support of this idea is the involvement of various PMCA isoforms both in cell proliferation [64,96,97] and apoptosis [9,76,98,99]. Suppressed proliferation of breast cancer MCF-7 cells or induced apoptosis in vascular smooth muscle cells via antisense-mediated PMCA inhibition were published earlier [97,99].…”

Calcium and glial cell death

“…Ca 2+ ionophores, chemotherapeutics, neurotoxins, pro-oxidants and other agents trigger apoptosis through this mechanism [63]. Ultimately, the apoptotic cascade activates proteases such as caspases and calpains which cleave numerous substrates including key components of the Ca 2+ signalling system such as the plasma membrane Ca 2+ -ATPase [64].…”

Mg(2+),ATP-dependent plasma membrane calcium pump of smooth muscle cells. ІІ. Regulation of activity

“…Після розрізання утворюється 120 кДа протеїн, який є конститутивно актив-ним, оскільки автоінгібіторний домен видалено [86] ] c у стані спокою, блокуючи Са 2+ -помпу [67]. Показано, що стероїдні гормони та-кож змінюють активність Са 2+ -помпи ПМ.…”