Beyond the Abstract - Endoglin suppresses human prostate cancer metastasis, by Michael Breen, MD, PhD Candidate and Raymond Bergan, MD

BERKELEY, CA ( - Prostate cancer (PCa) is the most common cancer of American men and the second leading cause of cancer death.(1)

Nearly all deaths result from the development of metastatic disease.(2) Cellular adhesion, migration, and invasion are complex biological processes, and their deregulation promotes the development of metastases. Endoglin is an auxiliary protein in the transforming growth factor β (TGF-β) receptor superfamily and a critical regulator of these processes in PCa cells .(3) This regulation occurs through modulation of signaling through Smad1.(4) Endoglin selectively promotes signaling through an anti-invasive pathway involving the TGF-β receptor ALK2 and the downstream effector Smad1 over the canonical, pro-invasive pathway through ALK5 and Smad3. Our recent work extends our knowledge of endoglin, demonstrating that endoglin suppresses the development of metastases in a mouse model of PCa.(5)

A curious finding arose from these studies. In the context of invasion endoglin opposes TGF-β function (TGF-β promotes invasion), yet TGF-β function is augmented by endoglin in the context of cell proliferation (TGF-β suppresses proliferation). This paradox highlights a salient point: nearly 20 years after the discovery that endoglin is part of the TGF-β signaling complex,(6) a clear molecular mechanism of endoglin function has yet to emerge. It is unknown how endoglin promotes one singaling pathway over another. Important pieces to this puzzle, however, may already be in place.

Endoglin has been well-studied in endothelial cells as mutations in the endoglin gene cause hereditary hemorrhagic telangiectasia,(7) an autosomal dominant disorder characterized by ateriovenous malformations and telangiectasias in the skin and solid organs. Endothelial cells balance TGF-β signaling though ALK5 and ALK1,(8) an endothelium-specific TGF-β receptor (TβR) that, among TβRs, is most homologous ALK2. ALK1 signaling is promoted by endoglin, while ALK5 signaling is inhibited.(9) Endoglin physically interacts with both ALK5(10) and ALK1,(11) and these interactions alter the phosphorylation pattern of ALK1, ALK5, and TβRII, a phenomenon with the potential to modulate receptor function.(12) Furthermore, endoglin’s short cytoplasmic domain, which is rich in serine and threonine residues, is specifically and sequentially phosphorylated by these receptors;(13) ALK5-mediated phosphorylation of endoglin on Ser634 or Ser635 is required for subsequent phosphorylation of distal threonines by ALK1. Further, threonine phosphorylation of endoglin rescues endothelial cells from detachment and growth inhibition mediated by constitutively active ALK1.(13) Thus, endoglin intimately and intricately interacts with TβRs and modulates their function.

Endoglin does not alter the ligand binding pattern of the TβRs with which it interacts.(14, 15) It does not interfere with receptor oligomerization.(14) The cytoplasmic domain of endoglin does, however, bind preferentially to inactive ALK5 (10) or ALK1.(11) Once ALK5 and ALK1 are activated, the cytoplasmic domains no longer associate. This set of findings is consistent with the notion that endoglin is altering the kinase activity and/or substrate specificity of the receptors with which it associates. Whether this occurs via competition for auto-phosphorylation sites, by inducing conformational changes in the receptor complex, by recruiting phosphatases, by altering substrate availability, by recruiting novel substrates, or by alternate mechanisms has not been established.

Selectivity and context dependence are also key features of endoglin function. Endoglin interacts with numerous receptors & ligands in the TGF-β family, though ligand binding largely occurs through interaction with other ligand-binding receptors.(14) Thus, ligand specificity is dictated by the interacting TβR. In monocytic cells, endoglin inhibits TGF-β mediated growth arrest and fibronectin synthesis, but not other TGF-β-promoted processes.(15) In endothelial cells, endoglin inhibits Smad3 transcriptional activity and function,(9, 11, 16) while in PCa cells Smad3 transcriptional activity appears to not be affected by endoglin.(4) TGF-β-mediated signaling through Smad2, by contrast, is promoted by endoglin,(10,17,18) though interestingly it is attenuated by endoglin in the absence of TGF-β.(10) It is tempting to speculate that the promotion of TGF-β-mediated growth inhibition by endoglin in PCa cells – which is in contrast to endoglin abrogation of TGF-β-mediated growth inhibition in endothelium – could occur through differential Smad involvement in the two cell types.

Finally, several TGF-β-independent functions of endoglin may also regulate metastatic behavior. Endoglin interacts via its cytoplasmic domain with the LIM domain-containing proteins zyxin and ZRP-1 to modulate focal adhesion composition and actin cytoskeletal architecture, respectively.(19, 20) Endoglin also promotes adhesion of cervical epithelial cells through a mechanism dependent on β1 integrin.(21) These findings warrant further study with respect to metastasis.

In summary, endoglin is a gatekeeper of TGF-β family signaling, integrating multiple inputs to selectively modulate downstream phenomena. Endoglin’s large number of potential partners, its unique expression pattern and interaction with these partners, likely plays a central role in dictating many of its cell type-specific effects. A more integrated understanding of endoglin function is likely to be fruitful in understanding how endoglin regulates metastatic behavior. This information is necessary to support the rational design of therapeutic regimens aimed at inhibiting metastasis.



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Written by:
Michael Breen, MD, PhD Candidate and Raymond Bergan, MD as part of Beyond the Abstract on This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.

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