Adaptor protein containing PH domain, PTB domain and leucine zipper (APPL1) regulates the protein level of EGFR by modulating its trafficking

Lee, Jae-Rin; Hahn, Hwa-Sun; Kim, Young-Hoon; Nguyen, Hong-Hoa; Yang, Jun‐Mo; Kang, Jong‐Sun; Hahn, Myong‐Joon

doi:10.1016/j.bbrc.2011.10.064

Cited by 20 publications

(15 citation statements)

References 30 publications

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“…There also appeared to be a deregulation of Akt signalling in prostate cancer cells, with control cells being responsive to transferrin endocytosis, but prostate cancer cells being unresponsive, despite having variable high or low amounts of Phospho-Akt/Akt. This altered signalling may be related to the intracellular location of the transferrin receptor that can be disturbed through changes in localisation or depletion of PtdIns3P (43) or affected through variable internalisation resulting from altered Appl1 or Rab5 expression (as is the case with epidermal growth factor receptor (44)), affecting receptor trafficking and signal modulation.…”

Section: Discussionmentioning

confidence: 99%

Altered Endosome Biogenesis in Prostate Cancer Has Biomarker Potential

Johnson

Parkinson-Lawrence

Shandala

et al. 2014

Molecular Cancer Research

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Prostate cancer is the second most common form of cancer in males, affecting one in eight men by the time they reach the age of 70. Current diagnostic tests for prostate cancer have significant problems with both false negatives and false positives, necessitating the search for new molecular markers. A recent investigation of endosomal and lysosomal proteins revealed that the critical process of endosomal biogenesis might be altered in prostate cancer. Here, a panel of endosomal markers was evaluated in prostate cancer and non-malignant cells and a significant increase in gene and protein expression was found for early, but not late endosomal proteins. There was also a differential distribution of early endosomes, and altered endosomal traffic and signalling of the transferrin receptors (TFRC and TFR2) in prostate cancer cells. These findings support the concept that endosome biogenesis and function is altered in prostate cancer. Microarray analysis of a clinical cohort confirmed the altered endosomal gene expression observed in cultured prostate cancer cells. Furthermore, in prostate cancer patient tissue specimens, the early endosomal marker and adaptor protein APPL1 showed consistently altered basement membrane histology in the vicinity of tumours and concentrated staining within tumour masses. These novel observations on altered early endosome biogenesis provide a new avenue for prostate cancer biomarker investigation and suggest new methods for the early diagnosis and accurate prognosis of prostate cancer.

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Section: Discussionmentioning

confidence: 99%

Altered Endosome Biogenesis in Prostate Cancer Has Biomarker Potential

Johnson

Parkinson-Lawrence

Shandala

et al. 2014

Molecular Cancer Research

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“…10, 11 Two isoforms, that is, APPL1 and APPL2, are localized in a subset of early endosomes as well as in the cytoplasm and in the nucleus. 10, 12 APPL1 participates in epidermal growth factor (EGF) receptor internalization 13 and in EGF-mediated promitotic signaling through its cytoplasmic-nuclear translocation after EGF stimulation. 10 Prosurvival and radioresistance might be potentially conferred by APPL1 via its regulation of the activity and substrate specifity of the serine/threonine kinase AKT.…”

mentioning

confidence: 99%

APPL proteins modulate DNA repair and radiation survival of pancreatic carcinoma cells by regulating ATM

et al. 2014

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Despite intensive multimodal therapies, the overall survival rate of patients with ductal adenocarcinoma of the pancreas is still poor. The chemo- and radioresistance mechanisms of this tumor entity remain to be determined in order to develop novel treatment strategies. In cancer, endocytosis and membrane trafficking proteins are known to be utilized and they also critically regulate essential cell functions like survival and proliferation. On the basis of these data, we evaluated the role of the endosomal proteins adaptor proteins containing pleckstrin homology domain, phosphotyrosine binding domain and a leucine zipper motif (APPL)1 and 2 for the radioresistance of pancreatic carcinoma cells. Here, we show that APPL2 expression in pancreatic cancer cells is upregulated after irradiation and that depletion of APPL proteins by small interfering RNA (siRNA) significantly reduced radiation survival in parallel to impairing DNA double strand break (DSB) repair. In addition, APPL knockdown diminished radiogenic hyperphosphorylation of ataxia telangiectasia mutated (ATM). Activated ATM and APPL1 were also shown to interact after irradiation, suggesting that APPL has a more direct role in the phosphorylation of ATM. Double targeting of APPL proteins and ATM caused similar radiosensitization and concomitant DSB repair perturbation to that observed after depletion of single proteins, indicating that ATM is the central modulator of APPL-mediated effects on radiosensitivity and DNA repair. These data strongly suggest that endosomal APPL proteins contribute to the DNA damage response. Whether targeting of APPL proteins is beneficial for the survival of patients with pancreatic adenocarcinoma remains to be elucidated.

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“…A systematic review and meta-analysis showed that higher levels of epidermal growth factor receptor predict for a poor prognosis in gc patients 36 . Lee et al 37 found that overexpression of appl1 enhances the stability of epidermal growth factor receptor in HeLa cells; appl1 depletion by small interfering rna reduces the epidermal growth factor receptor concentration.…”

Section: Discussionmentioning

confidence: 99%