SUMMARY
Lysine succinylation was recently identified as a post-translational modification in cells. However, the molecular mechanism underlying lysine succinylation remains unclear. Here, we show that carnitine palmitoyltransferase 1A (CPT1A) has lysine succinyl-transferase (LSTase) activity in vivo and in vitro. Using a stable isotope labeling by amino acid in cell culture (SILAC)-based proteomics approach, we found that 101 proteins were more succinylated in cells expressing wild-type (WT) CPT1A compared with vector control cells. One of the most heavily succinylated proteins in this analysis was enolase 1. We found that CPT1A WT succinylated enolase 1 and reduced enolase enzymatic activity in cells and in vitro. Importantly, mutation of CPT1A Gly710 (G710E) selectively inactivated carnitine palmitoyltransferase (CPTase) activity but not the LSTase activity that decreased enolase activity in cells and promoted cell proliferation under glutamine depletion. These findings suggest that CPT1A acts as an LSTase that can regulate enzymatic activity of a substrate protein and metabolism independent of its classical CPTase activity.
How mitochondrial metabolism is altered by oncogenic tyrosine kinases to promote tumor growth is incompletely understood. Here, we show that oncogenic HER2 tyrosine kinase signaling induces phosphorylation of mitochondrial creatine kinase 1 (MtCK1) on tyrosine 153 (Y153) in an ABL-dependent manner in breast cancer cells. Y153 phosphorylation, which is commonly upregulated in HER2 breast cancers, stabilizes MtCK1 to increase the phosphocreatine energy shuttle and promote proliferation. Inhibition of the phosphocreatine energy shuttle by MtCK1 knockdown or with the creatine analog cyclocreatine decreases proliferation of trastuzumab-sensitive and -resistant HER2 cell lines in culture and in xenografts. Finally, we show that cyclocreatine in combination with the HER2 kinase inhibitor lapatinib reduces the growth of a trastuzumab-resistant HER2 patient-derived xenograft. These findings suggest that activation of the phosphocreatine energy shuttle by MtCK1 Y153 phosphorylation creates a druggable metabolic vulnerability in cancer.
AIP1 is a conserved enhancer of ADF/cofilin-dependent actin dynamics. Caenorhabditis elegans has two AIP1 genes. They have overlapping functions, and ablation of both AIP1 isoforms causes embryonic lethality with strong defects in the assembly of muscle sarcomeres.
Pharmacological activation of the glycolytic enzyme PKM2 or expression of the constitutively active PKM1 isoform in cancer cells results in decreased lactate production, a phenomenon known as the PKM2 paradox in the Warburg Effect. Here we show that oxaloacetate (OAA) is a competitive inhibitor of human lactate dehydrogenase A (LDHA) and that elevated PKM2 activity increases
de novo
synthesis of OAA through glutaminolysis, thereby inhibiting LDHA in cancer cells. We also show that replacement of human LDHA with rabbit LDHA, which is relatively resistant to OAA inhibition, eliminated the paradoxical correlation between the elevated PKM2 activity and the decreased lactate concentration in cancer cells treated with a PKM2 activator. Furthermore, rabbit LDHA-expressing tumors displayed resistance to the PKM2 activator compared to human LDHA-expressing tumors in mice. These findings describe a mechanistic explanation for the PKM2 paradox by showing that OAA accumulates to inhibit LDHA following PKM2 activation.
The ducks (Anas platyrhynchos domestica) were domesticated from Mallard (Anas platyrhynchos). While the ducks bred in Japan and European countries are supposed to originate from the ducks in China and Southeast Asian countries, respectively, the molecular phylogeny of these ducks has not been studied. We herein showed the phylogenetic relationship from the nucleotide sequences within the mitochondrial DNA cytochrome b gene of +2 breed ducks. In this phylogenetic relationship, Japanese and Chinese ducks were found to belong to the same clade distinct from the clade containing European and Southeast Asian ducks. This finding demonstrates the heretofore supposed fact that domesticated ducks in China and Southeast Asian countries have been distributed to Japan and European countries, respectively. In addition, this phylogenetic tree revealed that the genetic constitution of Southeast Asian ducks is distinctly di#erent from that of Northeast Asian ducks.
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