PTPS Facilitates Compartmentalized LTBP1 S-Nitrosylation and Promotes Tumor Growth under Hypoxia

GTP cyclohydrolase I (GTPCH), 6-pyruvoyltetrahydropterin synthase (PTPS), and sepiapterin reductase (SR) are sequentially responsible for de novo synthesis of tetrahydrobiopterin (BH4), a known co-factor for nitric oxide synthase (NOS). The implication of BH4-biosynthesis process in tumorigenesis remains to be investigated. Here, we show that PTPS, which is highly expressed in early-stage colorectal cancer, is phosphorylated at Thr 58 by AMPK under hypoxia; this phosphorylation promotes PTPS binding to LTBP1 and subsequently drives iNOS-mediated LTBP1 S-nitrosylation through proximal-coupling BH4 production within the PTPS/iNOS/LTBP1 complex. In turn, LTBP1 S-nitrosylation results in proteasome-dependent LTBP1 protein degradation, revealing an inverse relationship between PTPS pT58 and LTBP1 stability. Physiologically, the repressive effect of PTPS on LTBP1 leads to impaired transforming growth factor β (TGF-β) secretion and thereby maintains tumor cell growth under hypoxia. Our findings illustrate a molecular mechanism underlying the regulation of LTBP1-TGF-β signaling by the BH4-biosynthesis pathway and highlight the specific requirement of PTPS for tumor growth. [Display omitted] •PTPS metabolic activity is required for colorectal tumor cell growth under hypoxia•AMPK phosphorylates PTPS-T58 and promotes PTPS-LTBP1 interaction•PTPS facilitates iNOS-mediated LTBP1 S-nitrosylation and LTBP1 protein degradation•PTPS-T58 phosphorylation promotes early colorectal cancer development PTPS is involved in de novo synthesis of tetrahydrobiopterin (BH4), an essential co-factor of nitric oxide synthase (NOS). Zhao et al. report that PTPS forms a complex with LTBP1 and facilitates iNOS-dependent LTBP1 compartmentalized S-nitrosylation and LTBP1 protein degradation. In consequence, PTPS prevents TGF-β secretion and TGF-β-induced growth arrest of tumor cells and promotes early colorectal tumor development.