Dataset Information

Schwann cell-specific deletion of the endosomal PI 3-kinase Vps34 leads to delayed radial sorting of axons, arrested myelination, and abnormal ErbB2-ErbB3 tyrosine kinase signaling.

ABSTRACT: The PI 3-kinase Vps34 (Pik3c3) synthesizes phosphatidylinositol 3-phosphate (PI3P), a lipid critical for both endosomal membrane traffic and macroautophagy. Human genetics have implicated PI3P dysregulation, and endosomal trafficking in general, as a recurring cause of demyelinating Charcot-Marie-Tooth (CMT) peripheral neuropathy. Here, we investigated the role of Vps34, and PI3P, in mouse Schwann cells by selectively deleting Vps34 in this cell type. Vps34-Schwann cell knockout (Vps34SCKO ) mice show severe hypomyelination in peripheral nerves. Vps34-/- Schwann cells interact abnormally with axons, and there is a delay in radial sorting, a process by which large axons are selected for myelination. Upon reaching the promyelinating stage, Vps34-/- Schwann cells are significantly impaired in the elaboration of myelin. Nerves from Vps34SCKO mice contain elevated levels of the LC3 and p62 proteins, indicating impaired autophagy. However, in the light of recent demonstrations that autophagy is dispensable for myelination, it is unlikely that hypomyelination in Vps34SCKO mice is caused by impaired autophagy. Endosomal trafficking is also disturbed in Vps34-/- Schwann cells. We investigated the activation of the ErbB2/3 receptor tyrosine kinases in Vps34SCKO nerves, as these proteins, which play essential roles in Schwann cell myelination, are known to traffic through endosomes. In Vps34SCKO nerves, ErbB3 was hyperphosphorylated on a tyrosine known to be phosphorylated in response to neuregulin 1 exposure. ErbB2 protein levels were also decreased during myelination. Our findings suggest that the loss of Vps34 alters the trafficking of ErbB2/3 through endosomes. Abnormal ErbB2/3 signaling to downstream targets may contribute to the hypomyelination observed in Vps34SCKO mice.

SUBMITTER: Logan AM

PROVIDER: S-EPMC5818149 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Schwann cell-specific deletion of the endosomal PI 3-kinase Vps34 leads to delayed radial sorting of axons, arrested myelination, and abnormal ErbB2-ErbB3 tyrosine kinase signaling.

Logan Anne M AM Mammel Anna E AE Robinson Danielle C DC Chin Andrea L AL Condon Alec F AF Robinson Fred L FL

Glia 20170615 9

The PI 3-kinase Vps34 (Pik3c3) synthesizes phosphatidylinositol 3-phosphate (PI3P), a lipid critical for both endosomal membrane traffic and macroautophagy. Human genetics have implicated PI3P dysregulation, and endosomal trafficking in general, as a recurring cause of demyelinating Charcot-Marie-Tooth (CMT) peripheral neuropathy. Here, we investigated the role of Vps34, and PI3P, in mouse Schwann cells by selectively deleting Vps34 in this cell type. Vps34-Schwann cell knockout (Vps34<sup>SCKO< ...[more]

PMID: 28617998

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Project description:Background:Despite growing therapeutic relevance of ERBB2 amplifications in colorectal cancer (CRC), little is known about ERBB2/ERBB3 mutations. We aimed to characterize these subsets of CRC. Methods:We performed a retrospective analysis of 419 CRC patients from MD Anderson (MDACC) and 619 patients from the Nurses' Health Study (NHS)/Health Professionals Follow-Up Study (HPFS) with tissue sequencing, clinicopathologic, mutational, and consensus molecular subtype (CMS) profiles of ERBB2/ERBB3 mutant patients. A third cohort of 1623 CRC patients with ctDNA assays characterized the ctDNA profile of ERBB2 mutants. All statistical tests were two-sided. Results:ERBB2 mutations occurred in 4.1% (95% confidence interval [CI] = 2.4% to 6.4%), 5.8% (95% CI = 4.1% to 8.0%), and 5.1% (95% CI = 4.0% to 6.2%) of MDACC, NHS/HPFS, and ctDNA patients, respectively. ERBB3 mutations occurred in 5.7% (95% CI = 3.7% to 8.4%, 95% CI = 4.0% to 7.8%) of patients in both tissue cohorts. Age, stage, and tumor location were not associated with either mutation. Microsatellite instability (MSI) was associated with ERBB2 (odds ratio [OR] = 5.98, 95% CI = 2.47 to 14.49, P < .001; OR = 5.13, 95% CI = 2.38 to 11.05, P < .001) and ERBB3 mutations (OR = 3.48, 95% CI = 1.51 to 8.02, P = .002; OR = 3.40, 95% CI = 1.05 to 10.96, P = .03) in both tissue cohorts. Neither gene was associated with TP53, APC, KRAS, NRAS, or BRAF mutations in tissue. However, PIK3CA mutations were strongly associated with ERBB2 mutations in all three cohorts (OR = 3.68, 95% CI = 1.83 to 7.41, P = .001; OR = 2.25, 95% CI = 1.11 to 4.58, P = .02; OR = 2.11, 95% CI = 1.25 to 3.58, P = .004) and ERBB3 mutations in the MDACC cohort (OR = 13.26, 95% CI = 5.27 to 33.33, P < .001). ERBB2 (P = 0.08) and ERBB3 (P = .008) mutations were associated with CMS1 subtype. ERBB2 (hazard ratio [HR] = 1.82, 95% CI = 1.23 to 4.03, P = .009), but not ERBB3 (HR = 0.88, 95% CI = 0.45 to 1.73, P = .73), mutations were associated with worse overall survival. Conclusions:MSI and PIK3CA mutations are associated with ERBB2/ERBB3 mutations. Co-occurring PIK3CA mutations may represent a second hit to oncogenic signaling that needs consideration when targeting ERBB2/ERBB3.

Dataset Information

Schwann cell-specific deletion of the endosomal PI 3-kinase Vps34 leads to delayed radial sorting of axons, arrested myelination, and abnormal ErbB2-ErbB3 tyrosine kinase signaling.

Publications

Schwann cell-specific deletion of the endosomal PI 3-kinase Vps34 leads to delayed radial sorting of axons, arrested myelination, and abnormal ErbB2-ErbB3 tyrosine kinase signaling.

Similar Datasets

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