Nuclear localization and possible functions of receptor tyrosine kinases

doi:10.1016/S0955-0674(03)00015-2

Current Opinion in Cell Biology

Volume 15, Issue 2, April 2003, Pages 143-148

https://doi.org/10.1016/S0955-0674(03)00015-2 Get rights and content

Abstract

Recent data have renewed interest in the possible nuclear localization of receptor tyrosine kinases, as well as their ligands. In one case, that of ErbB-4, the receptor is processed by two membrane-localized proteases to produce a soluble cytoplasmic domain fragment that includes the tyrosine kinase domain. This fragment, generated by a metalloprotease-dependent ectodomain cleavage followed by γ-secretase cleavage within the transmembrane domain, is also found in the nucleus. Three other receptor tyrosine kinases have been detected in the nucleus in the absence of proteolytic processing. In some instances, nuclear localization of receptor tyrosine kinases is growth-factor-dependent and tentative evidence suggests a role in transcription.

Introduction

Receptor tyrosine kinases (RTKs) are type I transmembrane molecules positioned at the cell surface to detect the presence of cognate growth factors produced in the extracellular milieu by neighboring cells. This recognition event activates the receptors’ intrinsic tyrosine kinase activity and initiates a network of signaling pathways that relay cell surface information to the nucleus and other points in the cell 1., 2.. Sequentially acting components, such as those of the Ras/MAPK (mitogen-activated protein kinase) pathway, or single component systems, such as the STAT pathway, constitute the mechanism by which this intracellular transfer of biochemical information is mediated. Current thinking is that the combinatorial information provided by these signal transduction pathways can explain the biological responses of cells to growth factors.

Growth factor–RTK complexes formed at the plasma membrane are not stagnant or restricted to the cell surface. That the complexes are rapidly internalized through clathrin-coated pits into an endocytic pathway has been recognized for several years. Subsequent to internalization, receptor complexes remain active, but eventually are sorted either to the lysosome and degraded or recycled back to the cell surface. More recently, evidence has begun to accumulate that the endocytic pathway may also be a site for the generation of signal transduction events 3., 4..

In this review, I describe recent data that combine RTK signaling and intracellular trafficking in a novel way. Recent reports indicate that receptors or fragments of receptors travel from the plasma membrane to the nucleus by different mechanisms and may, in the process, constitute biochemical signals that regulate cell function.

Section snippets

Routes to the nucleus

RTKs are found in the nucleus in two forms — either the intact molecule or its cytoplasmic domain fragment. While the means by which an intact receptor is translocated from the plasma membrane to the nucleus is not understood, the mechanism for fragment formation and translocation is, in general, known and supported by precedents of other cell-surface transmembrane molecules (Figure 1).

The protease-dependent route

The Notch receptor (a non-RTK) is cleaved following ligand binding such that two large fragments are produced by the sequential action of two distinct membrane-localized proteases, and one fragment is translocated to the nucleus 5., 6.. A similar scenario has been described for proteolytic processing of the Alzheimer’s precursor protein (APP). This mechanism has now been extended to ErbB-4 [7^••], an RTK that binds the growth factors heregulin/neuregulin, betacellulin, epiregulin and

The holoreceptor route

Three recent papers have added substantially to previously published data reporting the presence of full-length RTKs in the nucleus. In the case of ErbB-1, the epidermal growth factor (EGF) receptor, addition of the cognate ligand is required for nuclear localization, and, in fact, the complete ligand–receptor complex was reported to be present in the nucleus [29^••]. That this ligand–receptor complex is trafficked to the nucleus needs to be evaluated in light of older studies that defined the

Nuclear functions for receptor tyrosine kinases

Obviously, the physiologic importance of RTK nuclear localization has to be established by identifying their nuclear targets and demonstrating that these targets are required for a growth factor cellular response. In the case of ErbB-4 proteolytic processing, γ-secretase inhibition blocks heregulin-dependent growth inhibition of T47 cells [7^••]. Although the inhibitor could have other unknown effects, it did not influence EGF-dependent growth stimulation of the same cells. This remains the only

Conclusions

The new observations discussed above raise provocative ideas about the trafficking and signaling mechanisms of RTKs. The nuclear localization of other cell surface molecules or their cytoplasmic domain fragments are parallel examples of direct communication between these two cellular compartments. It seems logical to expect that additional examples, including other RTKs, will be added in the near future. The most important questions that remain to solidify the importance of these observations

Update

Previous reports have identified PSD-95 as a molecule that associates with a PDZ-domain recognition motif at the carboxyl terminus of ErbB-4 45., 46., 47.. Those reports suggest that ErbB-4 association with PSD-95 facilitates ligand-dependent activation of ErbB-4, ErbB-4 oligomerization, or both. A new report indicates that when the carboxy-terminal three residues of ErbB-4 are deleted, a mutation that prevents association with PDZ-domain-containing proteins, ErbB-4 proteolytic processing by

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

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of special interest
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of outstanding interest

Acknowledgements

Space limitations preclude highlighting all relevant work, particularly that reported before 2000. The author appreciates the contributions of Sue Carpenter and Lori Bennett in manuscript and figure preparation, respectively. I am also grateful to two colleagues, Bruce Carter and Scott Hiebert, for reading the manuscript and offering suggestions. The support of the National Cancer Institute, USA, (grant number CA97456) is acknowledged.

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Nuclear localization and possible functions of receptor tyrosine kinases

Abstract

Introduction

Section snippets

Routes to the nucleus

The protease-dependent route

The holoreceptor route

Nuclear functions for receptor tyrosine kinases

Conclusions

Update

References and recommended reading

Acknowledgements

Neuron

J. Biol. Chem.

J. Cell Biol.

Curr. Opin. Cell Biol.

J. Biol. Chem.

Cancer Res.

Cancer Res.

Clin. Cancer Res.

J. Biol. Chem.

Mol. Biol. Cell

Cell signaling by receptor tyrosine kinases

Cell

Signal transduction and the control of gene expression

Science

The EGF receptor: a nexus for trafficking and signaling

Bioessays

Signal transduction and endocytosis: close encounters of many kinds

Nature Rev.

γ-Secretase-mediated proteolysis in cell-surface-receptor signalling

Nature Rev.

γ-Secretase cleavage and nuclear localization of ErbB-4 receptor tyrosine kinase

Science

Untangling the ErbB signalling network

Nature Rev.

ErbB-4: a receptor tyrosine kinase

Inflamm Res.

Heregulin-dependent trafficking and cleavage of ErbB-4

J. Biol. Chem.

Tumor necrosis factor-α-converting enzyme is required for cleavage of ErbB4/HER4

J. Biol. Chem.

Novel ErbB4 juxtamembrane splice variants are frequently expressed in childhood medulloblastoma

Genes Chromosomes Cancer

ErbB4 and its isoforms. Selective regulation of growth factor responses by naturally occurring receptor variants

Trends Cardivasc. Med.

Presenilin-dependent γ-secretase-like intramembrane cleavage of ErbB4

J. Biol. Chem.

Expression of heregulin and ErbB/Her receptors in adult chinchilla cochlear and vestibular sensory epithelium

Hear Res.