Integrative proteomics reveals principles of dynamic phosphosignaling networks in human erythropoiesis
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Integrative proteomics reveals principles of dynamic phosphosignaling networks in human erythropoiesis. / Karayel, Oezge; Xu, Peng; Bludau, Isabell; Bhoopalan, Senthil Velan; Yao, Yu; Rita, Freitas Colaco Ana; Santos, Alberto; Schulman, Brenda A.; Alpi, Arno F.; Weiss, Mitchell J.; Mann, Matthias.
In: Molecular Systems Biology, Vol. 16, No. 12, 9813, 2020.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Integrative proteomics reveals principles of dynamic phosphosignaling networks in human erythropoiesis
AU - Karayel, Oezge
AU - Xu, Peng
AU - Bludau, Isabell
AU - Bhoopalan, Senthil Velan
AU - Yao, Yu
AU - Rita, Freitas Colaco Ana
AU - Santos, Alberto
AU - Schulman, Brenda A.
AU - Alpi, Arno F.
AU - Weiss, Mitchell J.
AU - Mann, Matthias
PY - 2020
Y1 - 2020
N2 - Human erythropoiesis is an exquisitely controlled multistep developmental process, and its dysregulation leads to numerous human diseases. Transcriptome and epigenome studies provided insights into system-wide regulation, but we currently lack a global mechanistic view on the dynamics of proteome and post-translational regulation coordinating erythroid maturation. We established a mass spectrometry (MS)-based proteomics workflow to quantify and dynamically track 7,400 proteins and 27,000 phosphorylation sites of five distinct maturation stages of in vitro reconstituted erythropoiesis of CD34(+) HSPCs. Our data reveal developmental regulation through drastic proteome remodeling across stages of erythroid maturation encompassing most protein classes. This includes various orchestrated changes in solute carriers indicating adjustments to altered metabolic requirements. To define the distinct proteome of each maturation stage, we developed a computational deconvolution approach which revealed stage-specific marker proteins. The dynamic phosphoproteomes combined with a kinome-targeted CRISPR/Cas9 screen uncovered coordinated networks of erythropoietic kinases and pinpointed downregulation of c-Kit/MAPK signaling axis as key driver of maturation. Our system-wide view establishes the functional dynamic of complex phosphosignaling networks and regulation through proteome remodeling in erythropoiesis.
AB - Human erythropoiesis is an exquisitely controlled multistep developmental process, and its dysregulation leads to numerous human diseases. Transcriptome and epigenome studies provided insights into system-wide regulation, but we currently lack a global mechanistic view on the dynamics of proteome and post-translational regulation coordinating erythroid maturation. We established a mass spectrometry (MS)-based proteomics workflow to quantify and dynamically track 7,400 proteins and 27,000 phosphorylation sites of five distinct maturation stages of in vitro reconstituted erythropoiesis of CD34(+) HSPCs. Our data reveal developmental regulation through drastic proteome remodeling across stages of erythroid maturation encompassing most protein classes. This includes various orchestrated changes in solute carriers indicating adjustments to altered metabolic requirements. To define the distinct proteome of each maturation stage, we developed a computational deconvolution approach which revealed stage-specific marker proteins. The dynamic phosphoproteomes combined with a kinome-targeted CRISPR/Cas9 screen uncovered coordinated networks of erythropoietic kinases and pinpointed downregulation of c-Kit/MAPK signaling axis as key driver of maturation. Our system-wide view establishes the functional dynamic of complex phosphosignaling networks and regulation through proteome remodeling in erythropoiesis.
KW - (Phospho)proteomics
KW - CRISPR
KW - Cas9 library screen
KW - human erythropoiesis
KW - SLC
KW - systems biology
KW - STEM-CELL-FACTOR
KW - ERYTHROID PROGENITOR CELLS
KW - C-KIT
KW - TYROSINE PHOSPHORYLATION
KW - TRANSCRIPTOME ANALYSES
KW - SIGNALING PATHWAYS
KW - PROTEIN EXPRESSION
KW - DISTINCT STAGES
KW - KINASE PATHWAY
KW - MICE LACKING
U2 - 10.15252/msb.20209813
DO - 10.15252/msb.20209813
M3 - Journal article
C2 - 33259127
VL - 16
JO - Molecular Systems Biology
JF - Molecular Systems Biology
SN - 1744-4292
IS - 12
M1 - 9813
ER -
ID: 255460860