The Nature of Intracrine Peptide Hormone Action

Abstract

Abstract-Current theory holds that peptide hormone action results from hormone binding to cell-surface receptors, with the generation of intracellular second messengers. However, a growing body of evidence suggests that intracellular peptide hormone, either internalized or synthesized in situ, can exert physiologically relevant effects. These effects are diverse and poorly understood. I propose that such intracrine action can serve to modulate cellular function over time and thereby play a role in biological memory of various sorts, in the maintenance of hormonal responsiveness, and in cellular differentiation. (Hypertension. 1999;34:534-538.)Key Words: intracrine Ⅲ peptides Ⅲ nucleus Ⅲ memory Ⅲ differentiation O ur laboratory introduced the term "intracrine" in 1984 to describe the actions of a peptide hormone within its cell of synthesis. 1 This concept was later explicitly expanded to include the intracellular action of internalized peptide hormones. 2 These formulations were based on our studies of the actions of intracellular angiotensin II. [1][2][3][4][5][6][7][8][9][10][11] Subsequently, evidence supporting intracrine action has been developed for a large number of peptide hormones and factors (for example, insulin, growth hormone, prolactin, nerve growth factor, interferon-␥, fibroblast growth factor [FGF], Tat protein, platelet-derived growth factor [PDGF], epidermal growth factor [EGF], parathyroid hormone-related protein [PTHrP], endogenous opiates, angiogenin, among others). [12][13][14][15][16][17][18][19][20][21][22][23][24] Although the intracellular actions of steroid hormones and their receptors have been studied intensively, the implications, if any, of intracrine peptide hormone action for normal or abnormal cellular physiology remain unclear. 23 Indeed, the default view appears to be that if such intracellular binding/action of peptide hormones exists at all, it represents a vestigial or unimportant aspect of biology.This view, however, is beginning to change as evidence mounts for the binding of a large number of peptide hormones to nuclei and other intracellular structures and for biological change associated with that binding. It would therefore appear useful at this time to reconsider the possible implications of intracrine peptide action.By way of review, one can note that peptide hormones have been reported to act intracellularly in the following ways: (1) binding to receptors in the endoplasmic reticulum soon after synthesis and generating second messengers, eg, PDGF-B/v-sis 24,25 ; (2) binding to intravesicular receptors after internalization, with subsequent generation of second messengers, eg, EGF in the absence of its membraneanchoring domain 26 ; (3) binding to receptors on the nuclear membrane, with the subsequent generation of second messengers, eg, insulin 17,27,28 ; (4) binding to nucleolar components, eg, FGF, PTHrP, angiogenin 13,18,20 ; and (5) binding to chromatin, eg, angiotensin II, PTHrP, nerve growth factor (NGF), EGF, and PDGF. 3,12,18,21,29 Given these observations,...

Implications of intracrine hormone action for physiology and medicine

“…In fact, many intracrines act in both fashions. Intracrines not infrequently are synthesized as isoforms, and in some cases, one isoform binds to an intracellular site in its cell of synthesis while another is secreted (47,51,52). In some cases, intracellular intracrine binding can be associated with clear biological effect.…”

“…In some cases, intracellular intracrine binding can be associated with clear biological effect. For example, the angiogenic protein angiogenin stimulates endothelial cell proliferation, either directly or indirectly, only after translocation to the nucleus of target endothelial cells (34,47,51,52). A similar dependence on nuclear translocation for the stimulation of proliferation is displayed by fibroblast growth factor-2 (FGF-2) (3).…”

“…In some cases, the intracellular action of an intracrine factor is similar to the action the factor exerts after cell membrane binding, but in some cases it is not. For example, parathyroid hormone-related protein inhibits mitogenesis of vascular smooth muscle cells following cell surface binding but stimulates mitosis following nuclear binding (1,2,47,51,52). Although in many cases biological action has been shown in association with intracellular intracrine binding, insufficient work has been done to date on the possible intracellular actions of peptide growth factors/hormones to make demonstrated intracellular biological function a requirement for ascribing intracrine status to a protein.…”

“…As it happens, a great structural diversity is to be found among intracrines. Cytokines such as interleuken-6, G protein-coupled receptor activating hormones such as angiotensin, growth factors such as insulin, as well as homeoproteins such as Engrailed 1 and 2 and Hoxa 5, and enzymes such as plateletderived endothelial cell growth factor (PDECGF-thymidine phosphorylase) all are putative intracrines (Table 1) (6,32,43,47,51,52,65,67). With the exception of renin-prorenin, all the factors listed in Table 1 have been reported in the nucleus.…”

“…Against this background, we have recently made proposals regarding the origin and actions of intracrines. These notions suggested 1) that higher order functionalities could result from the establishment of intracellular intracrine regulatory feedback loops, and 2) that some intracellular regulatory proteins may in fact be intracrines with extracellular functions (47,(50)(51)(52). Here the actions of several intracrines will be reviewed to begin to explore the potential relevance of intracrine functionality for physiology and medicine.…”