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

Polyanskaya, Sofya A, Moreno, Rosamaria Y, Lu, Bin, Feng, Ruopeng, Yao, Yu, Irani, Seema, Klingbeil, Olaf, Yang, Zhaolin, Wei, Yiliang, Demerdash, Osama E, Benjamin, Lukas A, Weiss, Mitchell J, Zhang, Yan Jessie, Vakoc, Christopher R (January 2022) SCP4-STK35/PDIK1L complex is a dual phospho-catalytic signaling dependency in acute myeloid leukemia. Cell Reports, 38 (2). p. 110233. ISSN 2211-1247

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Abstract

Acute myeloid leukemia (AML) cells rely on phospho-signaling pathways to gain unlimited proliferation potential. Here, we use domain-focused CRISPR screening and 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.

Item Type:	Paper
Subjects:	diseases & disorders > cancer > cancer types > acute myeloid leukemia Investigative techniques and equipment > CRISPR-Cas9 bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes
CSHL Authors:	Klingbeil, Olaf Vakoc, Christopher R. Polyanskaya, Sofya Lu, Bin Yang, Zhaolin Wei, Yiliang El Demerdash, Osama Benjamin, Lukas
Communities:	CSHL labs > Vakoc lab
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	11 January 2022
Date Deposited:	20 Jan 2022 15:07
Last Modified:	02 Feb 2022 18:16
PMCID:	PMC8796272
URI:	https://repository.cshl.edu/id/eprint/40491

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