Fig 6. FCHSD2 and Rab7 reciprocally regulate endocytic trafficking and lung cancer progression.

(A) FCHSD2 regulates multiple steps in endocytic trafficking. We previously showed that activation of FCHSD2 downstream of ERK1/2 increases the rate of clathrin-coated pit initiation and CME in NSCLC cells. Here, we report that FCHSD2 also increases the fraction of RTK trafficking from early endosomes to recycling endosomes and negatively regulates Rab7 activity, maturation of late endosomes/multivesicular bodies, and trafficking to lysosomes. Together, these activities of FCHSD2 increase the flux of RTKs through early endocytic pathways, thus altering their downstream signaling. Loss of FCHSD2 results in the accumulation of RTKs in late endosomes/lysosomes, increases levels of activated ERK1/2 in the nucleus, and enhances transcription and expression of c-Jun, EGFR, and MET. (B) Immunohistochemistry images and quantification (expressed as H-score) of FCHSD2 staining in representative lung tumor tissues. Scale bar, 100 μm. Two-tailed Student t tests were used to assess statistical significance. **P < 0.005, ***P < 0.0005. (C) Kaplan-Meier survival analysis of NSCLC or lung adenocarcinoma patients was performed in FCHSD2 or Rab7 high- and low-expression cohorts. The underlying data for this figure can be found in S1 Data. CCP, clathrin-coated pit; c-Jun, proto-oncogene c-Jun; CME, clathrin-mediated endocytosis; EE, early endosome; EGFR, epidermal growth factor receptor; ERK1/2, extracellular signal-regulated kinase 1 and 2; ETS1, protein C-ets-1; FCHSD2, FCH/F-BAR and Double SH3 Domain-Containing Protein; HR, hazard ratio; LE, late endosome; Lys, lysosomes; MET, proto-oncogene c-Met; MVB, multivesicular body; NSCLC, non-small-cell lung cancer; PM, plasma membrane; Rab7, Ras-related protein Rab-7A; RE, recycling endosome; RTK, receptor tyrosine kinase.