Three Key Residues Underlie the Differential Affinity of the TGFβ Isoforms for the TGFβ Type II Receptor

Crescenzo, Grégory De; Hinck, Cynthia S.; Shu, Zhang; Zúñiga, Jorge E.; Yang, Junhua; Tang, Yuping; Baardsnes, Jason; Mendoza, Valentín; Sun, LuZhe; López‐Casillas, Fernando; O’Connor-McCourt, Maureen D.; Hinck, Andrew P.

doi:10.1016/j.jmb.2005.10.022

Cited by 75 publications

(92 citation statements)

References 41 publications

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“…and TGF-b3, but not TGF-b2 (Supplementary Figure S1) (Komesli et al, 1998), due to amino-acid substitutions in TGF-b2 that reduce its affinity for the TbRII (De Crescenzo et al, 2006). Expression of the ligand trap significantly inhibited the ability of breast cancer cells to grow effectively in the bone and suppressed TGF-b-induced expression of PTHrP and IL-11, two osteoclastic factors that are important for the formation of breast cancer bone metastases (Manolagas, 1995;Yin et al, 1999;Sotiriou et al, 2001;Kakonen et al, 2002;Kang et al, 2003Kang et al, , 2005Deckers et al, 2006;Liao and McCauley, 2006).…”

Section: Discussionmentioning

confidence: 99%

Transforming growth factor-β1 is the predominant isoform required for breast cancer cell outgrowth in bone

Mourskaia

Dong

et al. 2008

Oncogene

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Transforming growth factor (TGF)-b signaling is a potent modulator of the invasive and metastatic behavior of breast cancer cells. Indeed, breast tumor responsiveness to TGF-b is important for the development of osteolytic bone metastases. However, the specific TGF-b isoforms that promote breast cancer outgrowth in bone is unknown. We demonstrate that expression of a TGF-b ligand trap, which neutralizes TGF-b1 and TGF-b3, in MDA-MB-231 breast cancer cells diminished their outgrowth in bone and reduced the severity of osteolytic lesion formation when compared with controls. We further show that a reduction or loss of TGF-b1 expression within the bone microenvironment of TGF-b1 þ /À and TGF-b1À/À mice significantly reduced the incidence of breast tumor outgrowth compared with wild-type animals. Interestingly, those tumors capable of growing within the tibiae of TGF-b1-deficient mice had upregulated expression of all three TGF-b isoforms. Finally, breast cancer cells expressing the TGF-b ligand trap showed a pronounced reduction in their ability to form osteolytic lesions when injected into the tibiae of TGF-b1 þ /À mice. Thus, our studies show that both host-and tumor-derived TGF-b expression plays a critical role during the establishment and outgrowth of breast cancer cells in bone.

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Section: Discussionmentioning

confidence: 99%

Transforming growth factor-β1 is the predominant isoform required for breast cancer cell outgrowth in bone

Mourskaia

Dong

et al. 2008

Oncogene

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“…1, E and F). In previous studies, substitution of these three residues was shown to be sufficient to confer TGF-␤2 with a T␤RII binding affinity comparable with TGF-␤1 and TGF-␤3 (39,40). Despite this, four additional residues peripheral to the T␤RII-binding site that differed in TGF-␤2 relative to TGF-␤1 were also substituted with the corresponding residues from TGF-␤1 (R26K, L89V, T95K, and I98V) (Fig.…”

Section: Isolation and Physical Characterization Of Mmtgf-␤2-7mmentioning

confidence: 95%

“…mmTGF-␤2 was the least desired variant, due to the expected low affinity for binding T␤RII. However, this was considered an addressable concern based on our prior studies, which demonstrated that substitution of Lys-25, Ile-92, and Lys-94 in TGF-␤2 with the corresponding residues in TGF-␤1 and TGF-␤3 engendered TGF-␤2 with the ability to bind T␤RII with high affinity (39,40).…”

Section: Isolation and Physical Characterization Of Mmtgf-␤2mentioning

confidence: 99%

“…Residues in the T␤RII binding interface are indicated by yellow shading. Residues substituted in mmTGF-␤2-7M relative to mmTGF-␤2 are highlighted in red, and include K25R, I92V, and N94R, which were shown previously to be necessary and sufficient for high affinity T␤RII binding (39,40). F, interface between TGF-␤3 and T␤RII, with Arg-25, Val-92, and Arg-94 highlighted by red labels.…”

Section: Arg25 Glu119mentioning

confidence: 99%

“…To confer mmTGF-␤2 with the ability to bind T␤RII with high affinity comparable with that of TGF-␤1 and TGF-␤3, the three residues in mouse TGF-␤2 shown previously to differ in the interface with T␤RII, Lys-25, Ile-92, and Asn-94 (40,42), were substituted with the corresponding residues from TGF-␤1 and -␤3, Arg-25, Val-92, and Arg-94 ( Fig. 1, E and F).…”

Section: Isolation and Physical Characterization Of Mmtgf-␤2-7mmentioning

confidence: 99%

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An engineered transforming growth factor β (TGF-β) monomer that functions as a dominant negative to block TGF-β signaling

Kim¹,

Barron²,

Hinck

et al. 2017

Journal of Biological Chemistry

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Edited by Norma AllewellThe transforming growth factor ␤ isoforms, TGF-␤1, -␤2, and -␤3, are small secreted homodimeric signaling proteins with essential roles in regulating the adaptive immune system and maintaining the extracellular matrix. However, dysregulation of the TGF-␤ pathway is responsible for promoting the progression of several human diseases, including cancer and fibrosis. Despite the known importance of TGF-␤s in promoting disease progression, no inhibitors have been approved for use in humans. Herein, we describe an engineered TGF-␤ monomer, lacking the heel helix, a structural motif essential for binding the TGF-␤ type I receptor (T␤RI) but dispensable for binding the other receptor required for TGF-␤ signaling, the TGF-␤ type II receptor (T␤RII), as an alternative therapeutic modality for blocking TGF-␤ signaling in humans. As shown through binding studies and crystallography, the engineered monomer retained the same overall structure of native TGF-␤ monomers and bound T␤RII in an identical manner. Cell-based luciferase assays showed that the engineered monomer functioned as a dominant negative to inhibit TGF-␤ signaling with a K i of 20 -70 nM. Investigation of the mechanism showed that the high affinity of the engineered monomer for T␤RII, coupled with its reduced ability to non-covalently dimerize and its inability to bind and recruit T␤RI, enabled it to bind endogenous T␤RII but prevented it from binding and recruiting T␤RI to form a signaling complex. Such engineered monomers provide a new avenue to probe and manipulate TGF-␤ signaling and may inform similar modifications of other TGF-␤ family members.The transforming growth factor ␤ isoforms, TGF-␤1, -␤2, and -␤3, are small secreted signaling proteins. Their overall structures are similar and consist of two cystine-knotted monomers tethered together by a single inter-chain disulfide bond (1). They coordinate wound healing, modulate immune cell function, maintain the extracellular matrix, and regulate epithelial and endothelial cell growth and differentiation (2). The TGF-␤s are synthesized as pre-pro-proteins, and after maturation, secretion, and release from their pro-domains (3), the mature homodimeric growth factors (GFs) 3 bind and bring together two single-pass transmembrane receptors, known as T␤RI and T␤RII, to form the signaling-competent T␤RI 2 -T␤RII 2 heterotetramer (4, 5). TGF-␤ GFs assemble T␤RI 2 -T␤RII 2 heterotetramer in a sequential manner, first by binding T␤RII followed by recruitment of T␤RI (6, 7). The stepwise assembly of T␤RII and T␤RI into a heterotetramer is driven by binding of T␤RI to a composite TGF-␤/T␤RII interface (Fig. 1A) (8, 9).The disruption or dysregulation of the TGF-␤ pathway is responsible for several human diseases. These include connec-

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TGF‐β superfamily co‐receptors in cancer

Pawlak

Blobe

2021

Developmental Dynamics

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Transforming growth factor‐β (TGF‐β) superfamily signaling via their cognate receptors is frequently modified by TGF‐β superfamily co‐receptors. Signaling through SMAD‐mediated pathways may be enhanced or depressed depending on the specific co‐receptor and cell context. This dynamic effect on signaling is further modified by the release of many of the co‐receptors from the membrane to generate soluble forms that are often antagonistic to the membrane‐bound receptors. The co‐receptors discussed here include TβRIII (betaglycan), endoglin, BAMBI, CD109, SCUBE proteins, neuropilins, Cripto‐1, MuSK, and RGMs. Dysregulation of these co‐receptors can lead to altered TGF‐β superfamily signaling that contributes to the pathophysiology of many cancers through regulation of growth, metastatic potential, and the tumor microenvironment. Here we describe the role of several TGF‐β superfamily co‐receptors on TGF‐β superfamily signaling and the impact on cellular and physiological functions with a particular focus on cancer, including a discussion on recent pharmacological advances and potential clinical applications targeting these co‐receptors.

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Three Key Residues Underlie the Differential Affinity of the TGFβ Isoforms for the TGFβ Type II Receptor

Cited by 75 publications

References 41 publications

Transforming growth factor-β1 is the predominant isoform required for breast cancer cell outgrowth in bone

Transforming growth factor-β1 is the predominant isoform required for breast cancer cell outgrowth in bone

An engineered transforming growth factor β (TGF-β) monomer that functions as a dominant negative to block TGF-β signaling

TGF‐β superfamily co‐receptors in cancer

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