Identification of insulin receptor substrate proteins as key molecules for the TβR‐V/LRP‐1‐mediated growth inhibitory signaling cascade in epithelial and myeloid cells

Huang, Shuan Shian; Leal, Sandra; Chen, Chunlin; Liu, I-Hua; Huang, Jung San

doi:10.1096/fj.04-1872fje

Cited by 33 publications

(68 citation statements)

References 65 publications

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“…EGF and FGFs are potent stimulators of the MAP kinase signaling cascade but are incapable of antagonizing IGFBP-3 growth inhibition. Furthermore, PI 3-kinase inhibitors do not affect IGFBP-3-induced growth inhibition in these cells [Huang et al, 2004a]. These observations suggest that the MAP kinase and PI 3-kinase signaling cascades, downstream of IRS proteins, are not involved in IGFBP-3 growth inhibition and in reversal of IGFBP-3 growth inhibition by insulin or IGF-I analogs.…”

Section: Irs Proteins Are Important For the Tbr-v-mediated Growth Inhmentioning

confidence: 72%

“…To test this hypothesis, we have studied the roles of IRS proteins in IGFBP-3-induced growth inhibition in Mv1Lu cells and 32D murine myeloid cells stably expressing IRS proteins and the insulin receptor. Our studies [Huang et al, 2004a] provided evidence that IRS proteins are critically important for IGFBP-3-induced growth inhibition and, furthermore, that IGFBP-3 inhibits cell growth by stimulating an okadaic acid-sensitive Ser/Thr-specific protein phosphatase (PPase) which dephosphorylates IRS proteins. A key piece of evidence is that stable transfection of 32D cells (which express TbR-V but do not produce endogenous IRS proteins and do not respond to IGFBP-3 growth inhibition) [Huang et al, 2004a] with IRS-1 or IRS-2 cDNA confers sensitivity to growth inhibition by IGFBP-3; this IRS-mediated growth inhibition is completely reversed by insulin in 32D myeloid cells stably expressing IRS-2 and the insulin receptor (IR).…”

Section: Irs Proteins Are Important For the Tbr-v-mediated Growth Inhmentioning

confidence: 83%

“…However, none of these ligands significantly inhibit growth of epithelial cells. Among the growth factors for epithelial cells (aFGF, bFGF, EGF, insulin, and IGF-I), only insulin and IGF-I analogs (with reduced affinity for IGFBP-3) are able to reverse growth inhibition induced by IGFBP-3 in Mv1Lu cells [Huang et al, 2004a]. EGF and FGFs are potent stimulators of the MAP kinase signaling cascade but are incapable of antagonizing IGFBP-3 growth inhibition.…”

Section: Irs Proteins Are Important For the Tbr-v-mediated Growth Inhmentioning

confidence: 99%

“…These observations suggest that the MAP kinase and PI 3-kinase signaling cascades, downstream of IRS proteins, are not involved in IGFBP-3 growth inhibition and in reversal of IGFBP-3 growth inhibition by insulin or IGF-I analogs. Thus, we hypothesized that the insulin receptor substrate (IRS) proteins, the signaling molecules shared by both the insulin receptor and IGF-I receptor signaling cascades, are directly involved in IGFBP-3-induced growth inhibition and its reversal by insulin and IGF-I analogs [Huang et al, 2004a]. To test this hypothesis, we have studied the roles of IRS proteins in IGFBP-3-induced growth inhibition in Mv1Lu cells and 32D murine myeloid cells stably expressing IRS proteins and the insulin receptor.…”

Section: Irs Proteins Are Important For the Tbr-v-mediated Growth Inhmentioning

confidence: 99%

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TGF‐β control of cell proliferation

Huang

2005

J of Cellular Biochemistry

201

264

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This article focuses on recent findings that the type V TGF-b receptor (TbR-V), which co-expresses with other TGF-b receptors (TbR-I, TbR-II, and TbR-III) in all normal cell types studied, is involved in growth inhibition by IGFBP-3 and TGF-b and that TGF-b activity is regulated by two distinct endocytic pathways (clathrin-and caveolar/lipidraft-mediated). TGF-b is a potent growth inhibitor for most cell types, including epithelial and endothelial cells. The signaling by which TGF-b controls cell proliferation is not well understood. Many lines of evidence indicate that other signaling pathways, in addition to the prominent TbR-I/TbR-II/Smad2/3/4 signaling cascade, are required for mediating TGF-b-induced growth inhibition. Recent studies revealed that TbR-V, which is identical to LRP-1, mediates IGFindependent growth inhibition by IGFBP-3 and mediates TGF-b-induced growth inhibition in concert with TbR-I and TbR-II. In addition, IRS proteins and a Ser/Thr-specific protein phosphatase(s) are involved in the TbR-V-mediated growth inhibitory signaling cascade. The TbR-V signaling cascade appears to cross-talk with the TbR-I/TbR-II, insulin receptor (IR), IGF-I receptor (IGF-IR), integrin and c-Met signaling cascades. Attenuation or loss of the TbR-V signaling cascade may enable carcinoma cells to escape from TGF-b growth control and may contribute to the aggressiveness and invasiveness of these cells via promoting epithelial-to-mesenchymal transdifferentiation (EMT). Finally, the ratio of TGF-b binding to TbR-II and TbR-I is a signal controlling TGF-b partitioning between two distinct endocytosis pathways and resultant TGF-b responsiveness. These recent studies have provided new insights into the molecular mechanisms underlying TGF-binduced cellular growth inhibition, cross-talk between the TbR-V and other signaling cascades, the signal that controls TGF-b responsiveness and the role of TbR-V in tumorigenesis.

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Section: Irs Proteins Are Important For the Tbr-v-mediated Growth Inhmentioning

confidence: 72%

Section: Irs Proteins Are Important For the Tbr-v-mediated Growth Inhmentioning

confidence: 83%

Section: Irs Proteins Are Important For the Tbr-v-mediated Growth Inhmentioning

confidence: 99%

Section: Irs Proteins Are Important For the Tbr-v-mediated Growth Inhmentioning

confidence: 99%

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TGF‐β control of cell proliferation

Huang

2005

J of Cellular Biochemistry

201

264

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“…Furthermore, LRP regulates signaling cascades by binding ECM molecules, such as fibronectin (29) and thrombospondin (30), and growth factors, such as platelet-derived growth factor (31,32), connective tissue growth factor (33), and TGF-␤ (34,35). Interestingly, several of these molecules also bind decorin (36 -39).…”

mentioning

confidence: 99%

The Low Density Lipoprotein Receptor-related Protein Functions as an Endocytic Receptor for Decorin

Brandan¹,

Retamal²,

Cabello-Verrugio³

et al. 2006

J. Biol. Chem.

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Decorin is a small leucine-rich proteoglycan that modulates the activity of transforming growth factor type ␤ and other growth factors and thereby influences the processes of proliferation and differentiation in a wide array of physiological and pathological reactions. Hence, understanding the regulatory mechanisms of decorin activity has broad implications. Here we report that the extracellular levels of decorin are controlled by receptor-mediated catabolism, involving the low density lipoprotein receptor family member, low density lipoprotein receptor-related protein (LRP). We show that decorin is endocytosed and degraded by C2C12 myoblast cells and that both processes are blocked by suppressing LRP expression using short interfering RNA. The same occurs with CHO cells, but not with CHO cells genetically deficient in LRP. Finally, we show that LRP-null CHO cells, transfected to express mini-LRP polypeptides containing either the second or fourth LRP ligand-binding domains, carry out decorin endocytosis and lysosomal degradation. These findings point to LRP-mediated catabolism as a new control pathway for the biological activities of decorin, specifically for its ability to influence extracellular matrix signaling.

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Commentary: Analysis of examination questions expose low faculty expectations

White

2011

Biochem Molecular Bio Educ

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I and other teaching faculty take pride in our ability to write creative and challenging examination questions. Our self-assessment is based on experience and our knowledge of our subject and discipline. Although our judgment may be correct, it is done usually in the absence of deep knowledge of what is known about the construction of high-quality questions and tests that assess student understanding. A recent study suggests that many of us may be deceiving ourselves.Momsen et al.[1] analyzed nearly 10,000 quiz and examination questions submitted by 50 faculty instructors of various undergraduate biology subjects including molecular biology. They classified each test item according to its cognitive level in the six categories of Bloom's taxonomy [2]. A question at the lowest level, knowledge, received a rating of 1 and successively higher levels of comprehension, application, analysis, synthesis, and evaluation received ratings of 2-6, respectively. Because examination questions are not of equal weight in grading, the authors took a weighted average to assign a Bloom level to the apparent cognitive expectations for students in a course. In addition, the authors evaluated the syllabi associated with the tests and determined the Bloom level that faculty conveyed to their students for the corresponding courses.The results are sobering. Of the 9,713 items classified, 93% were at Bloom's level 1 or 2, 6.7% at level 3, and <1% at level 4 or above that require higher order thinking skills. The mean for the entire set was 1.45, that is, mostly expecting recognition and recall of facts and definitions. When broken down by institution type, universities with doctoral programs scored the poorest with a rating of 1.38, whereas four-year colleges rated highest at 1.95, yet this is still low-level expectation by Bloom criteria. One might attribute this to the larger class size and the heavy reliance on multiple choice tests at universities; however, there was no relationship to class size in the dataset. The data show consistently that faculty expectations, as articulated in course syllabi, were higher than the level of performance they expected on examinations.

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Identification of insulin receptor substrate proteins as key molecules for the TβR‐V/LRP‐1‐mediated growth inhibitory signaling cascade in epithelial and myeloid cells

Cited by 33 publications

References 65 publications

TGF‐β control of cell proliferation

TGF‐β control of cell proliferation

The Low Density Lipoprotein Receptor-related Protein Functions as an Endocytic Receptor for Decorin

Commentary: Analysis of examination questions expose low faculty expectations

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