IGF-1-induced Processing of the Amyloid Precursor Protein Family Is Mediated by Different Signaling Pathways

Adlerz, Linda; Holback, Sofia; Multhaup, Gerd; Iverfeldt, Kerstin

doi:10.1074/jbc.m611183200

Cited by 70 publications

(61 citation statements)

References 47 publications

(53 reference statements)

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“…Previous investigations demonstrated that IR/IGF-1R-mediated signals increase APP α-and β-cleavage in cultured cells (Adlerz et al 2007;Costantini et al 2006). We therefore determined the abundance of βCTF (C-terminal fragment) and αCTF in the CNS of nIR −/− mice and respective controls (Fig.…”

Section: Neuronal Insulin Receptor Deletion Reduces Aβ Accumulation Imentioning

confidence: 99%

Insulin receptor signaling mediates APP processing and β-amyloid accumulation without altering survival in a transgenic mouse model of Alzheimer’s disease

Stöhr

Schilbach

Moll

et al. 2011

AGE

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Section: Neuronal Insulin Receptor Deletion Reduces Aβ Accumulation Imentioning

confidence: 99%

Insulin receptor signaling mediates APP processing and β-amyloid accumulation without altering survival in a transgenic mouse model of Alzheimer’s disease

Stöhr

Schilbach

Moll

et al. 2011

AGE

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“…The exact contribution of HER4 kinase activity to RIP remains to be determined, but an active HER4 kinase may facilitate recruitment and/or regulate activity of proteolytic complexes. For example the γ-secretase catalytic complex can be regulated by PI3K and MAPK activity [13], two common effectors of an activated HER4 pathway. In addition, and as been shown for the γ-secretase substrate amyloid precursor protein [14], phosphorylation of HER4 may serve to recruit the γ-secretase proteolytic complex.…”

Section: Mechanism Of Her4 Ripmentioning

confidence: 99%

HER4 Intracellular Domain (4ICD) Activity in the Developing Mammary Gland and Breast Cancer

Jones

2008

J Mammary Gland Biol Neoplasia

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The HER4 receptor tyrosine kinase was the final member of the EGFR-family to be discovered. In contrast to the other three members of this receptor family which function primarily as mitogenic effectors in the breast, HER4 appears to have multiple divergent functions in the normal and malignant breast. Interestingly, the majority of HER4 activities in the breast including pregnancy induced differentiation and lactation initiation, transcriptional activation, tumor cell proliferation, growth suppression, and induction of apoptosis appear to be mediated by an independently signaling soluble HER4 intracellular domain (4ICD). The 4ICD can accumulate within the nucleus or mitochondria and subcellular localization of 4ICD in part determines the physiological response of breast cells to 4ICD action. Here I will discuss the evidence supporting the role of 4ICD as the critical effector of HER4 signaling in the breast. In addition a developmental and temporal model of 4ICD action in the normal breast and during the progression of breast cancer will be presented to explain the paradox of divergent HER4 and 4ICD activities. KeywordsEGFR-family; Estrogen receptor; BCL-2 family; Apoptosis; Transcription Proteolytic Processing of HER4 to Generate a Soluble HER4 Intracellular Domain (4ICD)It is well accepted that the HER4 transmembrane receptor undergoes regulated intramembrane proteolysis (RIP) at the cell surface to release a soluble intracellular domain (ICD); a property that remains unique among EGFR-family members. An excellent review of the molecular details underlying HER4 RIP was recently published elsewhere [1]. In summary, ectodomain cleavage of the 180 kDa HER4 cell surface receptor is mediated by tumor necrosis factor α converting enzyme (TACE), a member of the ADAM metalloproteinase family referred to as ADAM17 [2]. Following TACE cleavage the ca. 120 kDa HER4 ectodomain, which includes the ligand binding region, is shed into the extracellular milieu while the remaining 80 kDa cleavage product (m80) is retained as a transmembrane peptide. The m80 harbors an active tyrosine kinase [3] and a carboxyl terminus with several potential tyrosine phosphorylation sites. Although the m80 is phosphorylated it remains unclear if this membrane tethered peptide transmits cellular signals. The HER4 m80 however is a substrate for presenilin-dependentsecretase cleavage. This RIP event results in membrane release of a soluble 4ICD. Depending upon specific cellular properties, that we are beginning to understand, membrane released 4ICD may translocate to the nucleus or remain in the cytosol where mitochondrial accumulation has e-mail: fjones@tulane.edu. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript been observed (Fig. 1). The 4ICD is emerging as a unique independently signaling molecule and the impact of 4ICD signaling in the breast will be discussed in detail here. [16][17][18]. Although there is increasing evidence to suggest that phosphorylation of γ-secretase and its substra...

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“…In our previous study, insulin and IGF-1 were shown to increase ectodomain shedding of endogenously expressed APP, APLP1, and APLP2 in SH-SY5Y cells (7). In addition, it was demonstrated that there are different signaling pathways involved in the processing of the different paralogues.…”

mentioning

confidence: 93%

“…This is interesting because a relationship between diabetes mellitus and AD has been suggested, and disturbed insulin levels and signaling in AD brains have been observed (6). In addition, insulin and the related insulin-like growth factor-1 (IGF-1) have even been shown to affect APP processing (7)(8).…”

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confidence: 99%

Insulin-like Growth Factor-1 (IGF-1)-induced Processing of Amyloid-β Precursor Protein (APP) and APP-like Protein 2 Is Mediated by Different Metalloproteinases

Jacobsen

Adlerz

Multhaup

et al. 2010

Journal of Biological Chemistry

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␣-Secretase cleavage of the amyloid precursor protein (APP) is of great interest because it prevents the formation of the Alzheimer-linked amyloid-␤ peptide. APP belongs to a conserved gene family including the two paralogues APP-like protein (APLP) 1 and 2. Insulin-like growth factor-1 (IGF-1) stimulates the shedding of all three proteins. IGF-1-induced shedding of both APP and APLP1 is dependent on phosphatidylinositol 3-kinase (PI3-K), whereas APLP2 shedding is independent of this signaling pathway. Here, we used human neuroblastoma SH-SY5Y cells to investigate the involvement of protein kinase C (PKC) in the proteolytic processing of endogenously expressed members of the APP family. Processing was induced by IGF-1 or retinoic acid, another known stimulator of APP ␣-secretase shedding. Our results show that stimulation of APP and APLP1 processing involves multiple signaling pathways, whereas APLP2 processing is mainly dependent on PKC. Next, we wanted to investigate whether the difference in the regulation of APLP2 shedding compared with APP shedding could be due to involvement of different processing enzymes. We focused on the two major ␣-secretase candidates ADAM10 and TACE, which both are members of the ADAM (a disintegrin and metalloprotease) family. Shedding was analyzed in the presence of the ADAM10 inhibitor GI254023X, or after transfection with small interfering RNAs targeted against TACE. The results clearly demonstrate that different ␣-secretases are involved in IGF-1-induced processing. APP is mainly cleaved by ADAM10, whereas APLP2 processing is mediated by TACE. Finally, we also show that IGF-1 induces PKC-dependent phosphorylation of TACE. Alzheimer disease (AD)2 is histopathologically characterized by the presence of amyloid plaques in the brain parenchyma. The major constituent of the plaques is the amyloid-␤ (A␤) peptide, which is derived from the A␤ precursor protein (APP) by ␤-and ␥-secretase cleavage in the amyloidogenic pathway (1). In addition to A␤, a larger secreted fragment, sAPP␤, and an intracellular fragment (APP intracellular domain) are formed. Proteolytic processing of APP occurs mainly by an alternative pathway. In this nonamyloidogenic pathway, A␤ formation is precluded because ␣-secretase cleaves APP in the middle of the A␤ region. In addition to sAPP␣, a small secreted peptide, p3, and APP intracellular domain are generated by subsequent ␥-secretase cleavage.APP belongs to a conserved gene family including the two mammalian paralogues amyloid precursor-like protein 1 and 2 (APLP1 and APLP2). The exact biological function of APP and its paralogues is still unknown, although several different studies have shown involvement of APP in cell adhesion, neurite outgrowth, synaptogenesis, modulation of synaptic plasticity, and neuroprotection (reviewed in Ref. 2). Homo-and heterotypic cis interactions of APP family members have been detected (3). APLP1 could also form trans interactions, suggesting a specific role of APLP1 in cell adhesion. Importantly, double knock-out studies in mi...

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IGF-1-induced Processing of the Amyloid Precursor Protein Family Is Mediated by Different Signaling Pathways

Cited by 70 publications

References 47 publications

Insulin receptor signaling mediates APP processing and β-amyloid accumulation without altering survival in a transgenic mouse model of Alzheimer’s disease

Insulin receptor signaling mediates APP processing and β-amyloid accumulation without altering survival in a transgenic mouse model of Alzheimer’s disease

HER4 Intracellular Domain (4ICD) Activity in the Developing Mammary Gland and Breast Cancer

Insulin-like Growth Factor-1 (IGF-1)-induced Processing of Amyloid-β Precursor Protein (APP) and APP-like Protein 2 Is Mediated by Different Metalloproteinases

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