MassIVE MSV000088383

Complete Public PXD029769

SCP4-STK35/PDIK1L complex is a dual phospho-catalytic signaling dependency in acute myeloid leukemia

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Description

Acute myeloid leukemia (AML) cells rely on phospho-signaling pathways to gain unlimited proliferation potential. Here, we used domain-focused CRISPR screening to identify the nuclear phosphatase SCP4 as a dependency in AML, yet this enzyme is dispensable in normal hematopoietic progenitor cells. Using CRISPR exon scanning and gene complementation assays, we show that the catalytic function of SCP4 is essential in AML. Through mass spectrometry analysis of affinity-purified complexes, we identify the kinase paralogs STK35 and PDIK1L as binding partners and substrates of the SCP4 phosphatase domain. We show that STK35 and PDIK1L function catalytically and redundantly in the same pathway as SCP4 to maintain AML proliferation and to support amino acid biosynthesis and transport. We provide evidence that SCP4 regulates STK35/PDIK1L through two distinct mechanisms: catalytic removal of inhibitory phosphorylation and by promoting kinase stability. Our findings reveal a phosphatase-kinase signaling complex that supports the pathogenesis of AML. [doi:10.25345/C5786Q] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: SCP4 ; STK35 ; PDIK1L ; acute myeloid leukemia ; phosphatase ; kinase ; complex ; dependency

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Principal Investigators:
(in alphabetical order) 		Christopher Vakoc, Cold Spring Harbor Laboratory, USA
Submitting User: oeldemer_cshl_edu
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