c-Src phosphorylation and activation of hexokinase promotes tumorigenesis and metastasis

Abstract

It is well known that c-Src has important roles in tumorigenesis. However, it remains unclear whether c-Src contributes to metabolic reprogramming. Here we find that c-Src can interact with and phosphorylate hexokinases HK1 and HK2, the rate-limiting enzymes in glycolysis. Tyrosine phosphorylation dramatically increases their catalytic activity and thus enhances glycolysis. Mechanistically, c-Src phosphorylation of HK1 at Tyr732 robustly decreases its Km and increases its Vmax by disrupting its dimer formation. Mutation in c-Src phosphorylation site of either HK1 or HK2 remarkably abrogates the stimulating effects of c-Src on glycolysis, cell proliferation, migration, invasion, tumorigenesis and metastasis. Due to its lower Km for glucose, HK1 rather than HK2 is required for tumour cell survival when glucose is scarce. Importantly, HK1-Y732 phosphorylation level remarkably correlates with the incidence and metastasis of various clinical cancers and may serve as a marker to predict metastasis risk of primary cancers.

Wnt‐induced activation of glucose metabolism mediates the in vivo neuroprotective roles of Wnt signaling in Alzheimer disease

“…In other tissues, mostly in the context of cancer models, activation of tyrosine kinases (e.g., c-Src) positively modulate the activity of HK. Interestingly, c-Src kinase activity also enhances the expression of lymphoid enhancer factor/T-cell factor, effectors of canonical Wnt signaling (Karni et al 2005;Yokoyama and Malbon 2009;Ramiere et al 2014;Zhang et al 2017). It remains to be determined whether Wnt signaling increases HK activity through c-Src tyrosine kinase.…”

TAT-Cx43266-283impairs metabolic plasticity in glioma stem cells in vitro and in vivo

“…1c). Because HK-1 and HK-2 activity is upregulated by c-Src phosphorylation 12 , the TAT-Cx43266-283-induced inhibition of c-Src 7,26 might hinder HK activity.…”

“…Because we found that TAT-Cx43266-283 altered the location of HKs (Fig. 1h), which are frequently associated with mitochondria 11,12 , we used a mitochondrial dye to follow the cellular distribution of these organelles. Importantly, these images revealed that TAT-Cx43266-283 treatment (50 μM, 24 h) modified the localization of mitochondria in GSCs but not in astrocytes ( Fig.…”

“…Emerging data suggest that, beyond cell-intrinsic factors, nutrient availability in the tumour microenvironment can also influence drug response, hampering the efficacy of common antitumoral drugs 10 . To investigate whether this was also the case for TAT-Cx43266-283, GSCs in complete medium were treated with 50 μM At the molecular level, GSCs adapted to glucose-only medium by upregulating glucose metabolism enzymes critical for cancer cells, such as HK-2 11,12 and glucose-6-phosphate-dehydrogenase (G6PD) 40,41 , the key and ratelimiting enzyme in the pentose phosphate pathway ( Supplementary Fig. 3b).…”

“…Since then, many studies have delved into the underlying mechanisms. c-Src can modulate glucose metabolism either indirectly through master transcription factors, such as c-myc 28 or hypoxia inducible factor 1ɑ (HIF-1ɑ) 29,30 , or directly through the regulation of the activity of key glucose metabolism proteins, such as HK-2 12 , which traps glucose intracellularly for further metabolization, or glucose-6-phosphate-dehydrogenase (G6PD) 31 , the key and rate-limiting enzyme in the pentose phosphate pathway.…”