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Spatial regulation of receptor tyrosine kinases in development and cancer - PubMed

  • ️Sun Jan 01 2012

Review

Spatial regulation of receptor tyrosine kinases in development and cancer

Jessica B Casaletto et al. Nat Rev Cancer. 2012.

Abstract

During development and tissue homeostasis, patterns of cellular organization, proliferation and movement are highly choreographed. Receptor tyrosine kinases (RTKs) have a crucial role in establishing these patterns. Individual cells and tissues exhibit tight spatial control of the RTKs that they express, enabling tissue morphogenesis and function, while preventing unwarranted cell division and migration that can contribute to tumorigenesis. Indeed, RTKs are deregulated in most human cancers and are a major focus of targeted therapeutics. A growing appreciation of the essential role of spatial RTK regulation during development prompts the realization that spatial deregulation of RTKs is likely to contribute broadly to cancer development and may affect the sensitivity and resistance of cancer to pharmacological RTK inhibitors.

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Figures

Figure 1
Figure 1. RTK surface abundance and distribution

Controlling receptor tyrosine kinase (RTK) surface abundance and distribution is a critical regulatory step since the activation of downstream signaling requires RTK dimerization. Locally high surface levels of an individual RTK may promote homodimerization and/or clustering (shown here), while high surface abundance of two or more RTKs may also increase heterodimer pairing. Distinct domains within the plasma membrane as well as the closely apposed and dynamic cortical actin cytoskeleton affect this key step in receptor activation.

Figure 2
Figure 2. Mechanisms controlling RTK surface abundance and distribution

A) Receptor tyrosine kinase (RTK) surface abundance is largely controlled by receptor endocytosis, which ultimately leads to receptor degradation or recycling. Stimulated (ligand-bound) or unstimulated (unbound) RTKs can be localized in plasma membrane domains such as clathrin-rich regions or lipid rafts, resulting in their endocytosis (via clathrin-coated pits or lipid rafts) or sequestration (in lipid rafts). B) In tumor cells, altered plasma membrane domains, cytoskeletal organization and/or vesicular trafficking can significantly affect RTK distribution and signaling by increasing the abundance/clustering of RTKs on the plasma membrane. In addition, RTK amplification or overexpression can lead to increased surface abundance, clustering and signaling as well as altered dimer pairing. In the example shown here, ErbB2 (represented here by the green RTK) is amplified or overexpressed, as it is in many human breast tumors. ErbB2 is a unique RTK in that it does not require ligand-binding for activation; thus, increased surface levels of ErbB2 lead to ligand-independent clustering and downstream signaling. ErbB2 amplification/overexpression also allows for increased heterodimerization with – and therefore activation of – other ErbB family members. Finally, mutations in RTKs themselves can affect their lateral or axial distribution and signaling.

Figure 3
Figure 3. Spatial control of RTK signaling by cell polarization

Localization of receptor tyrosine kinases (RTKs) to either the apical or basolateral surface dictates whether they can be activated by secreted ligands. For example, activation of RTKs can be promoted by directing their localization to either the apical or basolateral surface where they can interact with luminally- or basolaterally-provided ligands. Alternatively, activation of RTKs can be prevented by sequestering them from ligand by cell polarization (see example in text). Loss of polarity is a hallmark of epithelial cancers that most certainly yields altered spatial distribution of RTKs. Without defined apical and basolateral surfaces to which RTKs can be targeted and segregated from one another and/or their ligand(s), RTKs in depolarized cells can dimerize with receptors and/or be activated by ligands that are not normally available in a polarized cell, resulting in aberrant RTK signaling.

Figure 4
Figure 4. Spatial control of RTK signaling during tissue morphogenesis and homeostasis

A) The distribution and endocytic recycling of receptor tyrosine kinases (RTKs) at the front of a migrating cell (or group of cells) can promote continued RTK activation and migration toward secreted ligands, suggesting that RTK recycling to this region allows continued receipt of the directional cue. The example depicted here is that of epidermal growth factor receptor (EGFR) and platelet-derived growth factor (PDGF)/vascular endothelial growth factor (VEGF)-related receptor (PVR) in Drosophila border cell migration (see text). B) Spatial patterning of RTK activity plays a central role in tissue morphogenesis and homeostasis. In the intestine, the differential localization of Ephs and ephrins controls cell positioning along the crypt-villus axis. Bidirectional signaling establishes a physical boundary between adjacent EphB- and ephrin-B1-expressing cells via an E-cadherin-mediated mechanism that alters cell-cell adhesion between these cell types (see text). Modified with permission from Ref. #. C) VEGF receptor (VEGFR) helps define the identity of tip cells during angiogenic sprouting. Expression of VEGFR in the tip cell induces Delta-like 4 (DLL4), increasing Notch signaling and downregulating VEGFR2 expression in neighboring stalk cells. Tip cells localize VEGFR2 and VEGFR3 to filopodia to direct their migration towards a VEGF gradient. D) Activated RTKs can have distinct signaling outputs depending on their plasma membrane or endosomal localization. In fact, some RTKs – including EGFR and Trk – can assemble different signaling complexes depending on their axial localization (signaling responses A and B, see text). Several RTKs can also elicit distinct signaling responses from the nucleus (signaling response C, see Box 2).

Figure 5
Figure 5. Spatial deregulation of RTKs in tumor tissues

A) Loss of EphB-mediated spatial patterning in the small intestine can profoundly affect intestinal tumorigenesis. Top row: Fully malignant EphB-expressing tumor cells are restricted from expanding into the adjacent ephrin-B1-expressing compartment created by EphB-ephrin-B1 spatial patterning. Bottom row: When EphB-mediated spatial patterning is lost (ie. when EphB-signaling is lost), EphB-expressing tumor cells expand throughout the ephrin-B1 compartment; these tumors are larger, more numerous and more advanced. Modified with permission from Ref. #. B) Receptor tyrosine kinase (RTK) alterations in tumor cells can promote aberrant interactions with the surrounding stroma. For example, increased levels of EphB3 and/or EphB4 receptors in prostate cancer cells may allow these cells to exploit ephrin-B2 ligand produced by stromal fibroblasts to promote invasion. Indeed, the mis-expression of various Ephs/ephrins has been reported in prostate, colon, and breast cancer. C) The spatial distribution of RTKs within a tumor can play a key role in the development of resistance to targeted therapeutics. Tumor cells located at the tumor periphery can co-opt stromal ligand, whereas cells located in the tumor center may require ligand-independent mechanisms of activation. For example, expansion of MET-amplified (denoted by bolt), ErbB-inhibitor resistant lung tumor cells can be promoted by local, stroma-produced HGF.

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