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Page 4 of 14 Maisel et al. J Cancer Metastasis Treat 2019;5:7 I http://dx.doi.org/10.20517/2394-4722.2018.82

An event frequently observed in cancers such as breast, pancreatic, and lung is the localization of activated
receptor tyrosine kinases in the perinuclear space [43-45] . While not all of these receptors have been shown
to pass through the Golgi, they do appear to be subject to retrotranslocation as many of them are found in
the nucleus, including fibroblast growth factor receptor (FGFR), members of the ErbB family, and TGF-β
receptor, all of which will be further discussed below [41,46,47] .

Here, we explore a range of transmembrane receptors associated with cancer and metastasis, examining
their endogenous trafficking pathways, conditions in which this trafficking may be altered, and the
relationship between retrotranslocation, nuclear localization, and metastasis.

INSULIN RECEPTOR
The insulin receptor (InsR) is a receptor tyrosine kinase known to traffic to the perinuclear space (rather
[48]
than the TGN) and colocalize with SNARE proteins through a targeting motif in the carboxy terminus .
This perinuclear colocalization occurs in a subset of storage vesicles near the Golgi, driven by the high rates
of intravesicular cycling associated with InsR, as only 2-5 percent of the receptor is maintained at the cell
surface [49,50] . Intracellular InsR promotes the constitutive activation of AKT, resulting in glucose transporter
4 translocation, enhanced anchorage-independent growth, and altered acinar structure formation [50-52] .

FGFR
FGFR is a receptor tyrosine kinase highly involved in epithelial to mesenchymal transition (EMT) and
tumorigenesis, promoting signal transduction through mitogen-activated protein kinase (MAPK) and
[53]
β-catenin activity . Stimulation with ligand FGF1 results in receptor retention in Rab5-positive endosomes
in the perinuclear space (undetermined if in the Golgi apparatus) and promotes trafficking to the nucleus,
an event modulated by importin-β1 [46,54] . When bound to the ligand FGF2, FGFR is capable of inducing c-Jun
and cyclin D1 mRNA expression by acting as a transcription factor at the FGF2 promoter, an event similar
to that seen in EGFR [54-56] . Nuclear FGFR is highly associated with AKT-driven breast cancer metastasis to
the lung and pancreatic cancer cell invasion [57,58] . Importantly, neither the FGF ligands nor FGFR contain
[55]
a canonical nuclear localization sequence (NLS) , indicating that the nuclear localization is a result of
retrotranslocation driving activated receptors from endosomes in the perinuclear space toward the nucleus.

ERBB RECEPTORS
EGFR
ErbB1, also known as HER1 or EGFR is a single pass transmembrane receptor tyrosine kinase subject to
significant post-translational modifications, which affect both its activation and trafficking. Upon binding
a ligand, EGFR is subject to homo/heterodimerization, transphosphorylation, and is primarily trafficked to
the lysosome [59,60] . It is also capable of retrotranslocation, recycling, and other trafficking pathways, all of
which are highly dependent on the localization of EGFR within the cell and additional signal transduction
pathways activated in the cell [61-63] .

EGFR can bind a range of ligands, including epidermal growth factor (EGF), TGF-α, heparin-bound-
EGF (HB-EGF), β-cellulin (BTC), epiregulin (EPR), and amphiregulin (AR). Upon binding a ligand, ErbB
receptors dimerize and are subject to internalization and trafficking. Ligand binding triggers membrane
invagination within at least 30 s, a transient process that resets within approximately 15 min after exposure.
All ligands promote the transport of EGFR from the plasma membrane to EEA1-positive endosomes, though
AR is slightly less efficient at this [62,64] . EGF, HB-EGF, and BTC promote EGFR trafficking to the lysosome
[62]
for degradation, while TGF-α and EPR binding primarily promote EGFR recycling . EGFR-EGF binding
promotes activation of multiple signaling pathways including MAPK, PI3K, phospholipase C (PLCγ), and
AKT, leading to a host of potentially oncogenic activities when left unregulated. EGFR has been implicated