Membrane receptors mediating thyroid hormone action

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A recently identified thyroid hormone cell surface receptor on the extracellular domain of integrin αVβ3 leads in human cell lines to activation of the mitogen-activated protein kinase (MAPK) signal transduction cascade. Examples of MAPK-dependent thyroid hormone actions are plasma membrane ion pump stimulation and specific nuclear events. These events include serine phosphorylation of the nuclear thyroid hormone receptor, leading to coactivator protein recruitment and complex tissue responses, such as thyroid hormone-induced angiogenesis or tumor cell growth. The existence of this cell surface receptor means that the activity of administered hormone could be limited through structural modification of the molecule to reproduce or inhibit only those hormone actions initiated at the cell surface. Examples of such modifications are provided.

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Introduction: evidence for the existence of plasma membrane-binding sites for thyroid hormone

The well-studied actions of thyroid hormone begin with binding of T3 (3, 5, 3′-triiodo-L-thyronine) by heterodimeric nuclear thyroid hormone receptor (TR). There is consequent recruitment of coactivator proteins to the hormone–TR complex bound to promoter regions of thyroid hormone-responsive genes and induction of transcription 1, 2, 3, 4, 5. The existence of cell surface receptors for thyroid hormone has been acknowledged 3, 5, but only recently has the identity of such a receptor been

Putative receptor for thyroid hormone on integrin αVβ3

Integrins are ubiquitous heterodimeric structural proteins of the cell membrane that convey signals from the cell interior to the extracellular matrix (ECM) (inside-out) and from the ECM to the cell (outside-in) [21]. Evidence suggesting that a cell surface receptor site for thyroid hormone existed on an integrin accumulated from several sources before identification of the receptor on integrin αVβ3. Farwell et al. showed that L-thyroxine (T4) induced the interaction of integrins with the ECM

Nuclear receptors for thyroid hormone and the cell surface receptor

The existence of a superfamily of nuclear receptor proteins for thyroid hormone and for steroid hormones has been extensively documented and many of the functions of these transcriptionally active proteins are well understood 1, 3. In the absence of ligand, the principal receptors exist in a repressed state. Repression is imposed by the complexing of receptors with corepressor proteins, such as nuclear receptor corepressor (NCoR) and silencing mediator for retinoid acid and thyroid hormone

Thyroid hormone-directed phosphorylation of nucleoproteins other than TR; protein trafficking

It is not surprising, given the scope of cellular activities that thyroid hormone is known to have, that nuclear proteins in addition to TR are targets of T4-directed MAPK. Among these proteins are ER [13] and the oncogene suppressor protein, p53 [11], whose transcriptional activity is also changed by serine phosphorylation in thyroid hormone-treated cells [11]. Phosphorylation of p53 recovered from the cell nucleus is also directed from the cell surface by thyroid hormone [11]. In addition,

The cell surface receptor and cell membrane functions; roles of T3 and T4

Several laboratories have described actions of thyroid hormone on membrane ion pumps or channels 4, 52. These actions are summarized in Table 1. Some of these effects have been shown to be independent of TR and can be classified as membrane-initiated or non-genomic actions of the hormone [52]. The effects are non-genomic in that they are not primarily dependent upon intranuclear complexing of thyroid hormone and TR. Incerpi and co-workers have shown that the activity of the Na+/H+ antiporter is

Proposed contributions of membrane-initiated actions of thyroid hormone to cell or tissue function in the intact organism

Concentrations of thyroid hormone are stable in tissues and we presume that the actions of the hormone that have been described as acute are presumably ongoing and contribute to ‘basal activities’ of enzymes. Thus, the membrane-initiated actions of thyroid hormone described here can be considered factors that contribute to the setpoints of membrane ion pumps, such as Na/K-ATPase [58], the Na+/H+ antiporter and Ca2+-ATPase, or to basal levels of transcription of genes that contain TREs. In the

Other focuses of investigation of membrane-initiated actions of thyroid hormone

The structure–activity relationships of thyroid hormone analogs differ between the membrane receptor for the hormone and TR. Novel formulations of thyroid hormone are possible that are agonists exclusively at the cell surface, modeled after agarose–T4, or antagonists, structurally related to tetrac. For example, T4 has been conjugated to a biocompatible proprietary polymer and is angiogenically active in this form (S.A. Mousa, et al., unpublished data).

Although this review is focused on the

Conclusions

A receptor site for thyroid hormone has been identified on integrin αVβ3, a structural membrane protein that transduces its interactions with ECM proteins and other factors into intracellular events. Binding of thyroid hormone at the cell surface by the integrin leads to MAPK (ERK1/2) activation and downstream events involving nucleoproteins such as TR, ER and p53. Consequences of these membrane-initiated activities are thyroid hormone-induced angiogenesis and in vitro growth of certain tumor

Acknowledgements

This work was supported in part by the U.S. Department of Veterans Affairs and by the Candace King Weir Foundation.

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