Endosomal Adaptor Proteins APPL1 and APPL2 Are Novel Activators of β-Catenin/TCF-mediated Transcription

Rashid, Sajid; Pilecka, Iwona; Toruń, Anna; Olchowik, Marta; Bielińska, Beata; Miączyńska, Marta

doi:10.1074/jbc.m109.007237

Cited by 56 publications

(62 citation statements)

References 63 publications

(90 reference statements)

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“…[20][21][22][23][24][25] This protein is a member of the highly conserved RuvBl1/2 superfamily containing ATP binding motifs and DNA binding and helicase functions and an ability to form biologically relevant proteinprotein interactions with proteins implicated in cancer, including Myc, Tip60, APPL1, Pontin, and telomerase holoenzyme complexes. 20,23,[26][27][28][29] The validation of Reptin as an AGR2 binding protein gives rise to a potentially novel signaling complex involved in prometastatic cancer development. Our mapping of the determinants that mediate a specific Reptin-AGR2 protein-protein complex in vitro provides biochemical insights for understanding how the Reptin-AGR2 complex can be regulated in cells.…”

Section: Introductionmentioning

confidence: 99%

A Divergent Substrate-Binding Loop within the Pro-oncogenic Protein Anterior Gradient-2 Forms a Docking Site for Reptin

Maslon

Hrstka

Vojtesek

et al. 2010

Journal of Molecular Biology

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Anterior gradient-2 (AGR2) functions in a range of biological systems, including goblet cell formation, limb regeneration, inhibition of p53, and metastasis. There are no well-validated binding proteins for AGR2 protein despite the wealth of data implicating an important cellular function in vertebrates. The yeast two-hybrid system was used to isolate the ATP binding protein Reptin as an AGR2-interacting protein. AGR2 formed a stable complex in human cell lysates with Reptin, thus validating Reptin as an AGR2 binding protein in cells. Reptin was also shown to be overproduced in a panel of primary breast cancer biopsy specimens, relative to normal adjacent tissue from the same patient, suggesting a role in cancer growth in vivo. Mutations were made at the two ATP binding motifs in Reptin to evaluate the effects of ATP on Reptin-AGR2 complex stability. Loss-of-ATP binding mutations at the Walker A motif (K83A) or gain-of-ATP binding mutations at the Walker B motif (D299N) resulted in Reptin mutants with altered oligomerization, thermostability, and AGR2 binding properties. These data indicate that the two ATP binding motifs of Reptin play a role in regulating the stability of the AGR2-Reptin complex. The minimal region of AGR2 interacting with Reptin was localized using overlapping peptide libraries derived from the AGR2 protein sequence. The Reptin docking site was mapped to a divergent octapeptide loop in the AGR2 superfamily between amino acids 104 and 111. Mutations at codon Y104 or F111 in full-length AGR2 destabilized the binding of Reptin. These data highlight the existence of a protein docking motif on AGR2 and an ATP-regulated peptide-binding activity for Reptin. This knowledge has implications for isolating other AGR2-interacting proteins, for developing assays to isolate small molecules that target the Reptin ATP binding site, and for measuring the effects of the Reptin-AGR2 complex in cancer cell growth.

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Section: Introductionmentioning

confidence: 99%

A Divergent Substrate-Binding Loop within the Pro-oncogenic Protein Anterior Gradient-2 Forms a Docking Site for Reptin

Maslon

Hrstka

Vojtesek

et al. 2010

Journal of Molecular Biology

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“…In support of this, APPL1 interacts with and modulates the functions of histone deacetylases (HDAC)1-3[30, 31] to influence the expression of cyclin-dependent kinase inhibitor 1 (p21 CIP1 )[30]. APPL1 also forms a complex with the tumor repressor Reptin in complex with HDAC1 to relieve translational repression and promote transcription of Wnt-signaling target genes[32]. Moreover, APPL1 binds Dishevelled 2 (Dvl2) and enhances its ability to promote non-canonical Wnt signaling through the transcription factor activating protein 1 (AP-1).…”

Section: Appl1 In Signalingmentioning

confidence: 99%

APPL1 is a multifunctional endosomal signaling adaptor protein

Diggins

Webb

2017

Biochemical Society Transactions

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Endosomal adaptor proteins are important regulators of signaling pathways underlying many biological processes. These adaptors can integrate signals from multiple pathways via localization to specific endosomal compartments, as well as through multiple protein-protein interactions. One such adaptor protein that has been implicated in regulating signaling pathways is the adaptor protein containing a pleckstrin-homology (PH) domain, phosphotyrosine binding (PTB) domain, and leucine zipper motif 1 (APPL1). APPL1 localizes to a subset of Rab5-positive endosomes through its Bin-Amphiphysin-Rvs (BAR) and PH domains, and it coordinates signaling pathways through its interaction with many signaling receptors and proteins through its PTB domain. This review discusses our current understanding of the role of APPL1 in signaling and trafficking, as well as highlights recent work into the function of APPL1 in cell migration and adhesion.

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“…Indeed, the involvement of many endocytic proteins in the pathogenesis of cancer has been reported (Mosesson et al., 2008; Pyrzynska et al., 2009). Two homologous proteins APPL1 and APPL2 (adapter proteins containing pleckstrin homology domain, phosphotyrosine binding domain and leucine zipper motif) represent good examples of proteins actively participating in both endocytosis and cellular signaling (Banach‐Orlowska et al., 2009; Miaczynska et al., 2004; Rashid et al., 2009). In addition, some lines of evidence suggest a possible role of these proteins in cancer development and/or progression.…”

Section: Introductionmentioning

confidence: 99%

Multifunctional protein APPL2 contributes to survival of human glioma cells

et al. 2012

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Some endocytic proteins have recently been shown to play a role in tumorigenesis. In this study, we demonstrate that APPL2, an adapter protein with known endocytic functions, is upregulated in 40% cases of glioblastoma multiforme, the most common and aggressive cancer of the central nervous system. The silencing of APPL2 expression by small interfering RNAs (siRNAs) in glioma cells markedly reduces cell survival under conditions of low growth factor availability and enhances apoptosis (measured by executor caspase activity). Long-term depletion of APPL2 by short hairpin RNAs (shRNAs), under regular growth factor availability, suppresses the cell transformation abilities, assessed by inhibited colony formation in soft agar and by reduced xenograft tumor growth in vivo. At the molecular level, the negative effect of APPL2 knockdown on cell survival is not due to the alterations in AKT or GSK3β activities which were reported to be modulated by APPL proteins. Instead, we attribute the reduced cell survival upon APPL2 depletion to the changes in gene expression, in particular to the upregulation of apoptosis-related genes, such as UNC5B (a proapoptotic dependence receptor) and HRK (harakiri, an activator of apoptosis, which antagonizes anti-apoptotic function of Bcl2). In support of this notion, the loss of glioma cell survival upon APPL2 knockdown can be rescued either by an excess of netrin-1, the prosurvival ligand of UNC5B or by simultaneous silencing of HRK. Consistently, APPL2 overexpression reduces expression of HRK and caspase activation in cells treated with apoptosis inducers, resulting in the enhancement of cell viability. This prosurvival activity of APPL2 is independent of its endosomal localization. Cumulatively, our data indicate that a high level of APPL2 protein might enhance glioblastoma growth by maintaining low expression level of genes responsible for cell death induction.

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Endosomal Adaptor Proteins APPL1 and APPL2 Are Novel Activators of β-Catenin/TCF-mediated Transcription

Cited by 56 publications

References 63 publications

A Divergent Substrate-Binding Loop within the Pro-oncogenic Protein Anterior Gradient-2 Forms a Docking Site for Reptin

A Divergent Substrate-Binding Loop within the Pro-oncogenic Protein Anterior Gradient-2 Forms a Docking Site for Reptin

APPL1 is a multifunctional endosomal signaling adaptor protein

Multifunctional protein APPL2 contributes to survival of human glioma cells

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