Significance of Protein Kinase A in Cancer

Nesterova, Maria; Cho‐Chung, Yoon S.

doi:10.1007/978-1-59745-199-4_1

Cited by 2 publications

(1 citation statement)

References 133 publications

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“…Thus PKA phosphorylation would prevail over several modes of casp-9 activation. PKA is overexpressed in many cancers [41][42][43] and phosphorylation of casp-9 to prevent its full-scale activation could be one mechanism by which unregulated PKA promotes tumorigenesis, proliferation and transformation.…”

Section: Discussionmentioning

confidence: 99%

Phosphorylation by protein kinase A disassembles the caspase-9 core

Serrano

Hardy

2018

Cell Death Differ

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Caspases, the cysteine proteases which facilitate the faithful execution of apoptosis, are tightly regulated by a number of mechanisms including phosphorylation. In response to cAMP, PKA phosphorylates caspase-9 at three sites preventing caspase-9 activation, and suppressing apoptosis progression. Phosphorylation of caspase-9 by PKA at the functionally relevant site Ser-183 acts as an upstream block of the apoptotic cascade, directly inactivating caspase-9 by a two-stage mechanism. First, Ser-183 phosphorylation prevents caspase-9 self-processing and directly blocks substrate binding. In addition, Ser-183 phosphorylation breaks the fundamental interactions within the caspase-9 core, promoting disassembly of the large and small subunits. This occurs despite Ser-183 being a surface residue distal from the interface between the large and small subunits. This phosphorylation-induced disassembly promotes the formation of ordered aggregates around 20 nm in diameter. Similar aggregates of caspase-9 have not been previously reported. This two-stage regulatory mechanism for caspase-9 has likewise not been reported previously but may be conserved across the caspases.

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Section: Discussionmentioning

confidence: 99%