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Page 2 of 14 Maisel et al. J Cancer Metastasis Treat 2019;5:7 I http://dx.doi.org/10.20517/2394-4722.2018.82

INTRODUCTION
Retrograde transport is a process that involves secretory trafficking pathways from endosomes to the trans-
Golgi network (TGN), the Golgi to the endoplasmic reticulum (ER), and within the perinuclear space,
[1-4]
designed to maintain a steady-state localization of proteins . Upon internalization of a receptor, toxin,
or other constituent subject to intracellular trafficking, cargo is transported to the early endosomes. There,
cargo can be recycled to the plasma membrane (with or without passing through the recycling endosome),
transferred to a late endosome en route to the lysosome for degradation, or subject to retrotranslocation to
[5]
the trans-Golgi . Within the Golgi proteins can undergo post-translational modifications, be distributed
to their appropriate cellular localization (e.g., polarized membrane), or sent to the ER for re-folding or ER-
assisted degradation (ERAD). In this review, we focus on retrograde trafficking, not for the purposes of
protein homeostasis, but rather examining how activated receptor tyrosine kinases are trafficked towards the
nucleus upon internalization, where a host of signal transduction, DNA binding, and transcription result in
metastatic events. In multiple kinase receptor families, including the ErbB family, this alternative trafficking
results in endosomally-captured active receptors in the perinuclear space and nucleus. This trend is not
specific to solely receptor tyrosine kinases, as we also discuss the retrotranslocation of other transmembrane
proteins, such as the interleukin-2 receptor (ILR2) and the transforming growth factor β (TGF-β) receptor.
In addition to perinuclear localization, retrotranslocation is frequently associated with the upregulation and
constitutive activation of the phosphatidylinositol-3-OH kinase (PI3K)/protein kinase B (AKT) pathways,
known drivers of cancer metastasis. Taken together, we present the concept that retrotranslocation of
activated proteins, particularly receptor tyrosine kinases, augments AKT signaling and increases nuclear
transcription, resulting in cancer metastasis.

MEDIATORS OF RETROTRANSLOCATION
Internalization
Internalization of cargo, the first conserved step of retrograde trafficking (receptor tyrosine kinases require
activation, toxins do not) occurs in two primary formats - clathrin-mediated endocytosis (CME) or
retromer-assisted. Toxins (such as shiga, ricin, or cholera) and many receptor tyrosine kinases are subject to
retrotranslocation from the early endosome in clathrin-coated endosomes, while transmembrane receptors
such as wntless, β-secretase (BACE1), and TGN38 interact with the retromer complex from the early
endosome [6-11] . Trafficking constituents such as mannose 6 phosphate receptor and Vsp10 are directed from
late endosomes via the retromer complex [12-14] .

CME occurs when clathrin triskelions form a bilayered coat of polyhedral lattices surrounding an inner
coat of clathrin adaptors. Adaptors are then responsible for interacting with the cytoplasmic domains of
membrane-bound receptors, and in some instances, even appear to promote the binding of clathrin directly
[15]
to the receptor . Clathrin can interact not only with the cytoplasmic domain of receptors, but also with
post-translational modifications, and at the interface between endosomes and the TGN [3,16] . It has been
demonstrated that clathrin is frequently required for retrograde trafficking, both for endogenous cargo and
plasma-membrane-localized proteins [3,17] .

The retromer
In contrast to clathrin-mediated retrotranslocation, proteins can also be trafficked via the retromer complex.
The retromer is a three-protein complex consisting of Vsp26, 29, and 35, capable of binding the cytoplasmic
domain of transmembrane proteins located in endosomes without interacting with clathrin. Once bound,
the retromer interacts with a dimer of sorting nexin (SNX) family members (either SNX1/2 and SNX5/6)
to induce membrane curvature and direct retrograde trafficking away from lysosomal degradation [1,18] .
This trimer interacts with GTPases; Rab5 when interacting with the early endosome or Rab7 with the late
[2]
endosome . SNX proteins directly interact with the membrane, with a Bis/amphihysin/Rvs domain to sense