RT Journal Article
SR Electronic
T1 The SCP4-STK35/PDIK1L complex is a dual phospho-catalytic signaling dependency in acute myeloid leukemia
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.05.09.443327
DO 10.1101/2021.05.09.443327
A1 Sofya A. Polyanskaya
A1 Rosamaria Y. Moreno
A1 Bin Lu
A1 Ruopeng Feng
A1 Yu Yao
A1 Seema Irani
A1 Olaf Klingbeil
A1 Zhaolin Yang
A1 Yiliang Wei
A1 Osama E. Demerdash
A1 Lukas A. Benjamin
A1 Mitchell J. Weiss
A1 Yan Jessie Zhang
A1 Christopher R. Vakoc
YR 2021
UL http://biorxiv.org/content/early/2021/05/10/2021.05.09.443327.abstract
AB 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.Competing Interest StatementC.R.V. has received consulting fees from Switch, Roivant Sciences, and C4 Therapeutics, has served on the scientific advisory board of KSQ Therapeutics and Syros Pharmaceuticals, and has received research funding from Boehringer-Ingelheim during the conduct of the study.