TIE2-mediated tyrosine phosphorylation of H4 regulates DNA damage response by recruiting ABL1

Abstract

Membrane-bound enzyme relocates to the cell nucleus to modify chromatin, inducing cancer resistance to radiotherapy.

Caveolin‐1, cancer and therapy resistance

“…Glioblastoma -Silencing of key proliferative and cell survival pathways 188 -CAV1 is needed for TIE2 internalization which leads to improved DNA damage repair; inhibitors against CAV1 or TIE2 were able to re-sensitize cells to ionizing radiation 109,110 -Upregulation of CAV1 in tumorassociated myeloid cells in patient samples; inhibition of CAV1 restored function of myeloid cells 189 Leukemia -Overexpression of CAV1 correlated with MDR-1 expression in AML samples, which leads to a poor prognosis in leukemia 62,63 -CAV1 is upregulated in CLL patient samples 190…”

“…– CAV1 is needed for TIE2 internalization which leads to improved DNA damage repair; inhibitors against CAV1 or TIE2 were able to re‐sensitize cells to ionizing radiation…”

The Selective Tie2 Inhibitor Rebastinib Blocks Recruitment and Function of Tie2Hi Macrophages in Breast Cancer and Pancreatic Neuroendocrine Tumors

“…While biologics that sequester Tie2 ligands Ang1 or Ang2 may find clinical utility, there are additional ligands, including Ang4, which activate Tie2 receptors and escape capture by Ang1/Ang2 sequestering biologics (39,40). Additionally, extracellular signals including integrins (41,42) and lysyl oxidase (43,44) may also activate Tie2-mediated signaling, and internalized Tie2 signals to the DNA damage response (44). A selective small molecule inhibitor of Tie2 kinase would be capable of intercepting all of the above activating mechanisms, including those not blocked by the Ang-sequestering biologics.…”

Normalizing tumoral vessels to treat cancer: an out-of-the-box strategy involving TIE2 pathway

“…Nuclear TIE2 seems to act as a resistance factor to genotoxic stress by modifying the epigenetic pattern of tumor cells (29). In this regard, nuclear localization of TIE2 is related to enhanced DNA repair and radioresistance (29).…”

“…Nuclear TIE2 seems to act as a resistance factor to genotoxic stress by modifying the epigenetic pattern of tumor cells (29). In this regard, nuclear localization of TIE2 is related to enhanced DNA repair and radioresistance (29). Further investigation is needed to understand if nuclear TIE2 is a key player also in the resistance to DNA-damaging chemotherapeutic agents, and if this function will be jeopardized by the administration of ABTAA or similar TIE2-targeting agents.…”