BERKELEY, CA (UroToday.com) - 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.
- Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin 2010 Oct;60(5):277-300.
- Zelefsky MJ, Eastham JA, Sartor OA, Kantoff P. Cancer of the Prostate. In: Cancer: Principles & Practice of Oncology. Philadelphia: Wolters Kluwer/Lippincott Williams & Wilkins; 2008 p. 1392 - 1452.
- Liu Y, Jovanovic B, Pins M, Lee C, Bergan RC. Over expression of endoglin in human prostate cancer suppresses cell detachment, migration and invasion. Oncogene 2002 Nov;21(54):8272-8281.
- Craft CS, Romero D, Vary CPH, Bergan RC. Endoglin inhibits prostate cancer motility via activation of the ALK2-Smad1 pathway. Oncogene 2007 Nov;26(51):7240-7250.
- Lakshman M, Huang X, Ananthanarayanan V, Jovanovic B, Liu Y, Craft CS, Romero D, Vary CPH, Bergan RC. Endoglin suppresses human prostate cancer metastasis. Clin. Exp. Metastasis 2011 Jan;28(1):39-53.
- Cheifetz S, Bellón T, Calés C, Vera S, Bernabeu C, Massagué J, Letarte M. Endoglin is a component of the transforming growth factor-beta receptor system in human endothelial cells. J. Biol. Chem 1992 Sep;267(27):19027-19030.
- McAllister KA, Grogg KM, Johnson DW, Gallione CJ, Baldwin MA, Jackson CE, Helmbold EA, Markel DS, McKinnon WC, Murrell J. Endoglin, a TGF-beta binding protein of endothelial cells, is the gene for hereditary haemorrhagic telangiectasia type 1. Nat. Genet 1994 Dec;8(4):345-351.
- Goumans M, Valdimarsdottir G, Itoh S, Rosendahl A, Sideras P, ten Dijke P. Balancing the activation state of the endothelium via two distinct TGF-beta type I receptors. EMBO J 2002 Apr;21(7):1743-1753.
- Lebrin F, Goumans M, Jonker L, Carvalho RLC, Valdimarsdottir G, Thorikay M, Mummery C, Arthur HM, ten Dijke P. Endoglin promotes endothelial cell proliferation and TGF-beta/ALK1 signal transduction. EMBO J 2004 Oct;23(20):4018-4028.
- Guerrero-Esteo M, Sanchez-Elsner T, Letamendia A, Bernabeu C. Extracellular and cytoplasmic domains of endoglin interact with the transforming growth factor-beta receptors I and II. J. Biol. Chem 2002 Aug;277(32):29197-29209.
- Blanco FJ, Santibanez JF, Guerrero-Esteo M, Langa C, Vary CPH, Bernabeu C. Interaction and functional interplay between endoglin and ALK-1, two components of the endothelial transforming growth factor-beta receptor complex. J. Cell. Physiol 2005 Aug;204(2):574-584.
- Wrana JL, Ozdamar B, Le Roy C, Benchabane H. Signaling Receptors of the TGF-β Family. In: The TGF-β Family. Cold Spring Harbor, N.Y: Cold Spring Harbor Laboratory Press; 2008
- Koleva RI, Conley BA, Romero D, Riley KS, Marto JA, Lux A, Vary CPH. Endoglin structure and function: Determinants of endoglin phosphorylation by transforming growth factor-beta receptors. J. Biol. Chem 2006 Sep;281(35):25110-25123.
- Barbara NP, Wrana JL, Letarte M. Endoglin is an accessory protein that interacts with the signaling receptor complex of multiple members of the transforming growth factor-beta superfamily. J. Biol. Chem 1999 Jan;274(2):584-594.
- Lastres P, Letamendía A, Zhang H, Rius C, Almendro N, Raab U, López LA, Langa C, Fabra A, Letarte M, Bernabéu C. Endoglin modulates cellular responses to TGF-beta 1. J. Cell Biol 1996 Jun;133(5):1109-1121.
- Scherner O, Meurer SK, Tihaa L, Gressner AM, Weiskirchen R. Endoglin differentially modulates antagonistic transforming growth factor-beta1 and BMP-7 signaling. J. Biol. Chem 2007 May;282(19):13934-13943.
- Carvalho RLC, Jonker L, Goumans M, Larsson J, Bouwman P, Karlsson S, Dijke PT, Arthur HM, Mummery CL. Defective paracrine signalling by TGFbeta in yolk sac vasculature of endoglin mutant mice: a paradigm for hereditary haemorrhagic telangiectasia. Development 2004 Dec;131(24):6237-6247.
- Santibanez JF, Letamendia A, Perez-Barriocanal F, Silvestri C, Saura M, Vary CPH, Lopez-Novoa JM, Attisano L, Bernabeu C. Endoglin increases eNOS expression by modulating Smad2 protein levels and Smad2-dependent TGF-beta signaling. J. Cell. Physiol 2007 Feb;210(2):456-468.
- Conley BA, Koleva R, Smith JD, Kacer D, Zhang D, Bernabéu C, Vary CPH. Endoglin controls cell migration and composition of focal adhesions: function of the cytosolic domain. J. Biol. Chem 2004 Jun;279(26):27440-27449.
- Sanz-Rodriguez F, Guerrero-Esteo M, Botella L, Banville D, Vary CPH, Bernabéu C. Endoglin regulates cytoskeletal organization through binding to ZRP-1, a member of the Lim family of proteins. J. Biol. Chem 2004 Jul;279(31):32858-32868.
- Muenzner P, Rohde M, Kneitz S, Hauck CR. CEACAM engagement by human pathogens enhances cell adhesion and counteracts bacteria-induced detachment of epithelial cells. J. Cell Biol 2005 Aug;170(5):825-836.
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