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The role of endocytosis in activating and regulating signal transduction

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Abstract

Endocytosis is increasingly understood to play crucial roles in most signaling pathways, from determining which signaling components are activated, to how the signal is subsequently transduced and/or terminated. Whether a receptor-ligand complex is internalized via a clathrin-dependent or clathrin-independent endocytic route, and the complexes’ subsequent trafficking through specific endocytic compartments, to then be recycled or degraded, has profound effects on signaling output. This review discusses the roles of endocytosis in three markedly different signaling pathways: the Wnt, Notch, and Eph/Ephrin pathways. These offer fundamentally different signaling systems: (1) diffusible ligands inducing signaling in one cell, (2) membrane-tethered ligands inducing signaling in a contacting receptor cell, and (3) bi-directional receptor-ligand signaling in two contacting cells. In each of these systems, endocytosis controls signaling in fascinating ways, and comparison of their similarities and dissimilarities will help to expand our understanding of endocytic control of signal transduction across multiple signaling pathways.

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Abbreviations

ADAM:

A disintegrin and metallo-protease

AP1/2:

Adaptor protein one or two

Arf:

ADP-ribosylation factor

Arp2/3:

Actin-related protein 2/3

Cav1/2:

Caveolin one or two

CCP:

Clathrin-coated pit

CCV:

Clathrin-coated vesicle

CDR:

Circular dorsal ruffles (also known as waves)

CE:

Convergent extension

CLASP:

Clathrin-associated sorting proteins

CLIC-GEEC:

Clathrin-independent carrier/GPI-anchored protein-enriched early endosomal compartment

CME:

Clathrin-mediated endocytosis

CSL:

CBF1/Suppressor of Hairless/LAG-1

Dll1/3/4:

Delta-like one, three or four (Notch ligands)

Dsh/Dvl:

Disheveled

EEA1:

Early endosomal antigen one

EGF:

Epidermal growth factor

EGFR:

Epidermal growth factor receptor

Fc:

Fragment crystallizable region (tail region of antibody)

Flot1/2:

Flotillin one or two

GPI:

Glycosylphosphatidylinositol

GTPase:

Guanosine triphosphate hydrolase enzyme

Hek cells:

Human embryonic kidney cells

HeLa cells:

Cervical cancer cells from Henrietta Lacks

HGF:

Hepatocyte growth factor

Jag1/2:

Jagged one or two (Notch ligands)

LacZ:

Beta-d-galactosidase

LDL:

Low-denstity lipoprotein

Lef1:

Lymphoid enhancer-binding factor 1

Lqf:

Liquid facets (Drosophila epsin homolog)

NECD:

Notch extracellular domain

NEXT:

Notch extracellular truncation

NICD:

Notch intracellular domain

N-WASP:

Neural Wiskott-Aldrich syndrome protein (aka WASL, Wiskott-Aldrich syndrome-like)

PCP:

Planar cell polarity

PDGF:

Platelet-derived growth factor

PKC:

Protein kinase C

PM:

Plasma membrane

Ptc:

Patched (Shh receptor)

Rab11:

Rab-protein 11

Rac1:

RAS-related C3 botulinum substrate 1

Rin1:

Ras and Rab interactor one

Ror1/2:

Receptor tyrosine kinase-like orphan receptor one or two

Ryk:

Receptor-like tyrosine kinase

Shh:

Sonic hedgehog

TCF:

T-cell factor

TGF-β:

Transforming growth factor beta

Vav2:

Vav 2 guanine nucleotide exchange factor

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Acknowledgments

E.R.A. thanks Professor Urban Lendahl for scientific discussions and support, and Dr. Nicolas Fritz for fruitful discussions and constructive criticism of the manuscript.

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    Emma R. Andersson

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Andersson, E.R. The role of endocytosis in activating and regulating signal transduction. Cell. Mol. Life Sci. 69, 1755–1771 (2012). https://doi.org/10.1007/s00018-011-0877-1

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