<i>Appl1</i>and<i>Appl2</i>are Expendable for Mouse Development But Are Essential for HGF-Induced Akt Activation and Migration in Mouse Embryonic Fibroblasts

Tan, Yinfei; Xin, Xiaoban; Coffey, Francis; Wiest, David L.; Dong, Lily Q.; Testa, Joseph R.

doi:10.1002/jcp.25211

Cited by 14 publications

(11 citation statements)

References 35 publications

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“…Immunoblots were prepared with 30–50 µg of protein lysate sample, as previously described (Tan et al, ). Antibodies used for immunoblotting included a pan‐Akt antibody (cat.…”

Section: Methodsmentioning

confidence: 99%

Inactivation of Tp53 and Pten drives rapid development of pleural and peritoneal malignant mesotheliomas

Sementino

Menges

Kadariya

et al. 2018

Journal Cellular Physiology

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Malignant mesothelioma (MM) is a therapy-resistant cancer arising primarily from the lining of the pleural and peritoneal cavities. The most frequently altered genes in human MM are cyclin-dependent kinase inhibitor 2A (CDKN2A), which encodes components of the p53 (p14ARF) and RB (p16INK4A) pathways, BRCA1-associated protein 1 (BAP1), and neurofibromatosis 2 (NF2). Furthermore, the p53 gene (TP53) itself is mutated in ~15% of MMs. In many MMs, the PI3K-PTEN-AKT-mTOR signaling node is hyperactivated, which contributes to tumor cell survival and therapeutic resistance. Here, we demonstrate that the inactivation of both Tp53 and Pten in the mouse mesothelium is sufficient to rapidly drive aggressive MMs. Pten ;Tp53 mice injected intraperitoneally or intrapleurally with adenovirus-expressing Cre recombinase developed high rates of peritoneal and pleural MMs (92% of mice with a median latency of 9.4 weeks and 56% of mice with a median latency of 19.3 weeks, respectively). MM cells from these mice showed consistent activation of Akt-mTor signaling, chromosome breakage or aneuploidy, and upregulation of Myc; occasional downregulation of Bap1 was also observed. Collectively, these findings suggest that when Pten and Tp53 are lost in combination in mesothelial cells, DNA damage is not adequately repaired and genomic instability is widespread, whereas the activation of Akt due to Pten loss protects genomically damaged cells from apoptosis, thereby increasing the likelihood of tumor formation. Additionally, the mining of an online dataset (The Cancer Genome Atlas) revealed codeletions of PTEN and TP53 and/or CDKN2A/p14ARF in ~25% of human MMs, indicating that cooperative losses of these genes contribute to the development of a significant proportion of these aggressive neoplasms and suggesting key target pathways for therapeutic intervention.

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“…Immunoblots were prepared with 30–50 µg of protein lysate sample, as previously described (Tan et al, ). Antibodies used for immunoblotting included a pan‐Akt antibody (cat.…”

Section: Methodsmentioning

confidence: 99%

Inactivation of Tp53 and Pten drives rapid development of pleural and peritoneal malignant mesotheliomas

Sementino

Menges

Kadariya

et al. 2018

Journal Cellular Physiology

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“…Our results here, together with our previous work (Broussard et al, 2012), indicate that APPL1 can be a negative regulator of cell migration, depending on the ECM substrate and the integrin repertoire (Figs 1 and 2). By contrast, other studies have reported that APPL1 is a positive regulator of migration (Tan et al, 2016(Tan et al, , 2010. There are some key differences between these studies that may explain the contradictory results, including the use of embryonic mouse cells (Tan et al, 2010) versus human cancer cells ( Fig.…”

Section: Discussionmentioning

confidence: 95%

“…Thus, whereas decreased internalization of α5β1 integrin leads to slower migration on FN, perhaps APPL1 also alters trafficking of the HGF receptor MET, which could lead to an increase in HGFinduced migration (Ménard et al, 2014;Muller et al, 2013). Tan et al (2016) also implicated APPL2 in cell migration, acting redundantly with APPL1. However, although APPL2 is expressed in HT1080 cells, a 50% knockdown of APPL2 alone, or in APPL1depleted cells, showed no effect on migration speed on FN (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Our group has previously shown that APPL1 expression hinders cell migration by reducing Akt activation, thereby impairing adhesion turnover (Broussard et al, 2012). In addition, studies employing a genetic approach show that both APPL1 and APPL2 are necessary for hepatocyte growth factor (HGF)-induced migration of murine embryonic fibroblasts (MEFs) (Tan et al, 2016(Tan et al, , 2010. A recent study demonstrated that a subset of Arf6 compartments that colocalizes with APPL1 mediates recycling of β1 integrins, suggesting that APPL1 may be involved in integrin trafficking (Chen et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

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α5β1 integrin trafficking and Rac activation are regulated by APPL1 in a Rab5-dependent manner to inhibit cell migration

Diggins

Kang

Weaver

et al. 2018

Journal of Cell Science

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Cell migration is a tightly coordinated process that requires the spatiotemporal regulation of many molecular components. Because adaptor proteins can serve as integrators of cellular events, they are being increasingly studied as regulators of cell migration. The adaptor protein containing a pleckstrin-homology (PH) domain, phosphotyrosine binding (PTB) domain, and leucine zipper motif 1 (APPL1) is a 709 amino acid endosomal protein that plays a role in cell proliferation and survival as well as endosomal trafficking and signaling. However, its function in regulating cell migration is poorly understood. Here, we show that APPL1 hinders cell migration by modulating both trafficking and signaling events controlled by Rab5 in cancer cells. APPL1 decreases internalization and increases recycling of α5β1 integrin, leading to higher levels of α5β1 integrin at the cell surface that hinder adhesion dynamics. Furthermore, APPL1 decreases the activity of the GTPase Rac and its effector PAK, which in turn regulate cell migration. Thus, we demonstrate a novel role for the interaction between APPL1 and Rab5 in governing crosstalk between signaling and trafficking pathways on endosomes to affect cancer cell migration.This article has an associated First Person interview with the first author of the paper.

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“…Furthermore, as a crucial element of protein trafficking and cell signaling, APPL1 can mediate the Akt signaling pathway to augment various pathophysiological processes (Tan et al, 2016 ; Wang et al, 2016 ). Thus, based on our APPL1 and phosphorylated Akt results, we investigated whether the APPL1/Akt signaling pathway mediated the effect of curcumin on IR-induced AKI.…”

Section: Discussionmentioning

confidence: 99%

Molecular Mechanisms of Curcumin Renoprotection in Experimental Acute Renal Injury

et al. 2017

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As a highly perfused organ, the kidney is especially sensitive to ischemia and reperfusion. Ischemia-reperfusion (IR)-induced acute kidney injury (AKI) has a high incidence during the perioperative period in the clinic and is an important link in ischemic acute renal failure (IARF). Therefore, IR-induced AKI has important clinical significance and it is necessary to explore to develop drugs to prevent and alleviate IR-induced AKI. Curcumin [diferuloylmethane, 1,7-bis(4-hydroxy-3-methoxiphenyl)-1,6-heptadiene-3,5-dione)] is a polyphenol compound derived from Curcuma longa (turmeric) and was shown to have a renoprotective effect on ischemia-reperfusion injury (IRI) in a previous study. However, the specific mechanisms underlying the protective role of curcumin in IR-induced AKI are not completely understood. APPL1 is a protein coding gene that has been shown to be involved in the crosstalk between the adiponectin-signaling and insulin-signaling pathways. In the study, to investigate the molecular mechanisms of curcumin effects in kidney ischemia/reperfusion model, we observed the effect of curcumin in experimental models of IR-induced AKI and we found that curcumin treatment significantly increased the expression of APPL1 and inhibited the activation of Akt after IR treatment in the kidney. Our in vitro results showed that apoptosis of renal tubular epithelial cells was exacerbated with hypoxia-reoxygenation (HR) treatment compared to sham control cells. Curcumin significantly decreased the rate of apoptosis in renal tubular epithelial cells with HR treatment. Moreover, knockdown of APPL1 activated Akt and subsequently aggravated apoptosis in HR-treated renal tubular epithelial cells. Conversely, inhibition of Akt directly reversed the effects of APPL1 knockdown. In summary, our study demonstrated that curcumin mediated upregulation of APPL1 protects against ischemia reperfusion induced AKI by inhibiting Akt phosphorylation.

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Appl1andAppl2are Expendable for Mouse Development But Are Essential for HGF-Induced Akt Activation and Migration in Mouse Embryonic Fibroblasts

Cited by 14 publications

References 35 publications

Inactivation of Tp53 and Pten drives rapid development of pleural and peritoneal malignant mesotheliomas

Inactivation of Tp53 and Pten drives rapid development of pleural and peritoneal malignant mesotheliomas

α5β1 integrin trafficking and Rac activation are regulated by APPL1 in a Rab5-dependent manner to inhibit cell migration

Molecular Mechanisms of Curcumin Renoprotection in Experimental Acute Renal Injury

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