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ROR1 sustains caveolae and survival signalling as a scaffold of cavin-1 and caveolin-1

Tomoya Yamaguchi1, Can Lu1, Lisa Ida1

  • 1Division of Molecular Carcinogenesis, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.

Nature Communications
|January 5, 2016
PubMed

Insights

Receptor tyrosine kinase-like orphan receptor 1 (ROR1) acts as a scaffold protein, stabilizing caveolae structures. This novel function of ROR1 may offer a new therapeutic strategy against lung adenocarcinoma, particularly EGFR-TKI resistant forms.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is implicated in prosurvival signaling in lung adenocarcinoma, downstream of NKX2-1/TTF-1.
  • Caveolae are critical cellular structures involved in various signaling pathways.

Purpose of the Study:

  • To elucidate the novel function of ROR1 beyond its kinase activity.
  • To investigate the role of ROR1 in the structural integrity and function of caveolae.
  • To explore the therapeutic potential of targeting ROR1's scaffold function in lung adenocarcinoma.

Main Methods:

  • Investigated ROR1's interaction with cavin-1 and caveolin-1 (CAV1).
  • Assessed the impact of ROR1 on CAV1 stability and lysosomal degradation.
  • Examined the effect of ROR1 inhibition on prosurvival signaling pathways (e.g., AKT) and resistance to EGFR-TKIs.

Main Results:

  • ROR1 functions as a scaffold for cavin-1 and CAV1, independent of its kinase activity.
  • This scaffold function prevents lysosomal degradation of CAV1, maintaining caveolae structures.
  • ROR1 inhibition overcomes resistance to EGFR-TKIs by disrupting bypass signaling through RTKs like MET and IGF-IR.

Conclusions:

  • ROR1 possesses a kinase-independent scaffold function crucial for caveolae stability and prosurvival signaling.
  • Targeting ROR1's scaffold function presents a promising therapeutic strategy for lung adenocarcinoma, especially in overcoming TKI resistance.
  • ROR1's onco-embryonic expression pattern makes its scaffold function an attractive target for cancer treatment.

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