Function of Flotillins in Receptor Tyrosine Kinase Signaling and Endocytosis: Role of Tyrosine Phosphorylation and Oligomerization

Kurrle, Nina; John, Bincy; Meister, Melanie; Tikkanen, Ritva

doi:10.5772/48598

Cited by 14 publications

(22 citation statements)

References 153 publications

(275 reference statements)

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“…We found that LRAP interacted with CD63 protein in membrane protein extracts obtained from cementoblasts. Intriguingly, previous studies have shown that under stimulation with growth factors, such as hepatocyte growth factor (HGF) and EGF, flotillin‐1 can be quickly translocated from the plasma membrane to late endosomes/lysosomes positives for CD63 (Neumann‐Giesen et al, ; Babuke et al, ; Kurrle et al, ). Therefore, future functional studies should be considered to demonstrate CD63 as a player in the flotillin‐assisted endocytosis and in biological effects stimulated by LRAP in OCCM‐30 cells.…”

Section: Discussionmentioning

confidence: 99%

Leucine-Rich Amelogenin Peptide (LRAP) Uptake by Cementoblast Requires Flotillin-1 Mediated Endocytosis

et al. 2016

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Basic, pre-clinical, and clinical studies have documented the potential of amelogenin, and its variants, to affect cell response and tissue regeneration. However, the mechanisms are unclear. Thus, the aim of the present study was to identify, in cementoblasts, novel binding partners for an alternatively spliced amelogenin form (Leucine-Rich Amelogenin Peptide-LRAP), which is supposed to act as a signaling molecule in epithelial-mesenchymal interactions. LRAP-binding protein complexes from immortalized murine cementoblasts (OCCM-30) were achieved by capture affinity assay (GST pull down) and proteins present in these complexes were identified by mass spectrometry and immunoblotting. Flotillin-1, which functions as a platform for signal transduction, vesicle trafficking, endocytosis, and exocytosis, was identified and confirmed by co-precipitation and co-localization assays as a protein-binding partner for LRAP in OCCM-30 cells. In addition, we found that exogenously added GST-LRAP recombinant protein was internalized by OCCM-30 cells, predominantly localized in the perinuclear region and, that inhibition of flotillin1-dependent functions by small interference RNA (siRNA) methodology significantly affected LRAP uptake and its biological properties on OCCM-30 cells, including LRAP effect on the expression of genes encoding osteocalcin (Ocn), bone sialoprotein (Bsp), and runt-related transcription factor 2 (RunX2). In conclusion, LRAP uptake by cementoblast involves flotillin-assisted endocytosis, which suggests an involvement of LRAP in lipid-raft-dependent signaling pathways which are mediated by flotillin-1. J. Cell. Physiol. 232: 556-565, 2017. © 2016 Wiley Periodicals, Inc.

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Section: Discussionmentioning

confidence: 99%

Leucine-Rich Amelogenin Peptide (LRAP) Uptake by Cementoblast Requires Flotillin-1 Mediated Endocytosis

et al. 2016

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“…Structurally, flotillins are composed of two domains, the function of which has not been clarified in detail. The N-terminal SPFH (stomatin/prohibitin/flotillin/HflK/C) domain contains the sites for acylation [ 11 , 24 , 25 , 27 , 31 ], whereas the so-called flotillin domain in the C-terminus mediates the oligomerization and contains Ala-Glu repeats and phosphorylatable tyrosines that are important for flotillin function [ 11 , 12 , 26 , 32 , 33 , 34 ]. Both flotillins are ubiquitously expressed, conserved among species and homologous to each other [ 35 , 36 ], although they appear to be functionally distinct.…”

Section: The Flotillin Protein Familymentioning

confidence: 99%

Endocytic Trafficking of Membrane-Bound Cargo: A Flotillin Point of View

2014

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The ubiquitous and highly conserved flotillin proteins, flotillin-1 and flotillin-2, have been shown to be involved in various cellular processes such as cell adhesion, signal transduction through receptor tyrosine kinases as well as in cellular trafficking pathways. Due to the fact that flotillins are acylated and form hetero-oligomers, they constitutively associate with cholesterol-enriched lipid microdomains. In recent years, such microdomains have been appreciated as platforms that participate in endocytosis and other cellular trafficking steps. This review summarizes the current findings on the role of flotillins in membrane-bound cargo endocytosis and endosomal trafficking events. We will discuss the proposed function of flotillins in endocytosis in the light of recent findings that point towards a role for flotillins in a step that precedes the actual endocytic uptake of cargo molecules. Recent findings have also revealed that flotillins may be important for endosomal sorting and recycling of specific cargo molecules. In addition to these aspects, the cellular trafficking pathway of flotillins themselves as potential cargo in the context of growth factor signaling will be discussed.

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“…For a review on flotillin functions in general, the reader is referred to two recent review articles [1,2]. …”

Section: Introductionmentioning

confidence: 99%

Flotillins in Receptor Tyrosine Kinase Signaling and Cancer

Banning

Kurrle

Meister

et al. 2014

Cells

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Flotillins are highly conserved proteins that localize into specific cholesterol rich microdomains in cellular membranes. They have been shown to be associated with, for example, various signaling pathways, cell adhesion, membrane trafficking and axonal growth. Recent findings have revealed that flotillins are frequently overexpressed in various types of human cancers. We here review the suggested functions of flotillins during receptor tyrosine kinase signaling and in cancer. Although flotillins have been implicated as putative cancer therapy targets, we here show that great caution is required since flotillin ablation may result in effects that increase instead of decrease the activity of specific signaling pathways. On the other hand, as flotillin overexpression appears to be related with metastasis formation in certain cancers, we also discuss the implications of these findings for future therapy aspects.

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Function of Flotillins in Receptor Tyrosine Kinase Signaling and Endocytosis: Role of Tyrosine Phosphorylation and Oligomerization

Cited by 14 publications

References 153 publications

Leucine-Rich Amelogenin Peptide (LRAP) Uptake by Cementoblast Requires Flotillin-1 Mediated Endocytosis

Leucine-Rich Amelogenin Peptide (LRAP) Uptake by Cementoblast Requires Flotillin-1 Mediated Endocytosis

Endocytic Trafficking of Membrane-Bound Cargo: A Flotillin Point of View

Flotillins in Receptor Tyrosine Kinase Signaling and Cancer

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