Migration, invasion and metastasis of tumor cells are responsible for most cancer-related mortality. Understanding how tumor cells acquire a migratory phenotype to become invasive and metastatic is crucial to developing effective strategies to block tumor progression. The first step in tumor cell invasion is dissolution of cell-cell adhesions in favor of cell-matrix adhesions that support cell migration. Once the cell has freed itself from the original tumor mass, it reorganizes its actin cytoskeleton forming membrane protrusions stabilized by adhesions to the extracellular matrix (ECM) that facilitate directed cell movement ().1
Cells migrate in response to extracellular cues such as growth factors, which bind their cognate receptor protein tyrosine kinases (RTKs) at the cell surface. RTK activation initiates signaling cascades that contribute to the destabilization of cell-cell adhesions and promote migration by influencing the reorganization of the actin cytoskeleton. Activation of RTKs typically involves receptor dimerization and subsequent trans-autophosphorylation of a series of tyrosine residues within the cytoplasmic domain of the RTK.2,3
The phosphotyrosine residues provide docking sites for the recruitment and activation of downstream signaling molecules containing SH2 or PTB domains.3
Activation of RTKs initiates multiple signaling pathways, but for simplicity, we will comment only on a subset of signaling molecules downstream of RTKs that influence cell motility. These include phospholipase C γ1 (PLCγ1), protein kinase Cs (PKCs), Src family kinases, Rho GTPases, catenins and IQGAP1 ().
Figure 1 Cell migration regulated by cell-cell and cell-ECM adhesion is altered in cancer. In response to migratory stimuli such as growth factors, cells polarize and send out membrane protrusions, which are stabilized by cell-extracellular matrix (ECM) adhesion (more ...)
Figure 2 Migratory signals transduced by the RTKs, RPTPs and cadherins are altered by cleavage. RTK downstream signaling by Src family kinases (SFKs) and PLCγ1 contribute to destabilization of cell-cell adhesions and promotion of migration, respectively. (more ...)
At the plasma membrane, the activity of RTKs is counter-balanced by receptor protein tyrosine phosphatases (RPTPs).4,5
RPTPs serve to terminate signals generated by RTKs, maintaining appropriate spatial and temporal signaling; if RTKs are the gas pedal for migration, RPTPs are the brakes. In tumor cells, RTK activity is often constitutive due to RTK gene mutation or amplification.3,6
This gives tumor cells an advantage over non-cancerous cells because the tumor cells no longer depend on growth factors to drive cell migration. RPTPs are often inactivated in human tumors,7,8
at both the genetic and epigenetic level, suggesting they are important regulators of tumor progression. Tumor-specific methylation within the 5′ regulatory region of genes encoding RPTPs has been observed in several human cancers resulting in loss of gene expression. Furthermore, inactivating mutations in the RPTP tumor suppressor genes LAR, PTPρ, PTPδ and DEP-1 have been identified in several human cancers. Changes in RPTPs at the protein level such as cleavage of PTPµ and PTPκ have been associated with tumor progression.7,8
For a comprehensive review of RPTPs associated with human cancers, see Julien et al. For microarray studies focused on PTPs in cancer see Tiscornia et al.9
and McArdle et al.10
Cell adhesion molecules (CAMs) are transmembrane glycoproteins expressed on the cell surface that mediate both cell-cell and cell-ECM interactions. Cell-cell CAMs include the cadherins and immunoglobulin (Ig)-like CAMs while integrins mediate cell-ECM adhesions.11
In general, cadherin based cell-cell adhesions are associated with stable cell-cell adherens junctions that suppress a migratory phenotype while the integrin-mediated cell-ECM adhesions are associated with the promotion of cell motility ().12
Tyrosine phosphorylation of the cadherin/catenin complex by activated RTKs, or by members of the Src family of tyrosine kinases (activated downstream of RTKs) destabilizes cell-cell adhesions to promote cell-matrix adhesion.13
RPTP activity tends to stabilize cell-cell adhesion and suppresses migration.
There is accumulating evidence in the literature that cell-cell CAMs, including RPTPs and cadherins, are downregulated in tumor cells by proteolytic cleavage at the cell surface.14,15
Proteolysis results in shedding of the extracellular, adhesive segment and displacement of the intracellular segment, altering its subcellular localization and the availability of substrates or binding partners. Cleavage of most cell-cell CAMs follows a model similar to that described for the Notch receptor.14–16
Notch is processed by three sequential proteolytic events, a process also known as regulated intramembrane proteolysis.17
The first cleavage event takes place in the trans-Golgi and is mediated by a furin-like convertase. The second cleavage occurs at the plasma membrane and involves a member of the disintegrin and metalloprotease (ADAM) family of proteases and results in shedding of the extracellular domain (ECD). ECD shedding creates a membrane-tethered intermediate that is further processed by the γ-secretase-presenilin complex within the residual transmembrane domain. γ-secretase cleavage of Notch releases a cytoplasmic fragment of Notch which is then able to translocate into the nucleus where it controls transcription.17
We hypothesize that cleavage of RPTPs and cadherins coupled with constitutive activation of RTKs is a way for tumor cells to ensure invasive and metastatic success. Cleavage of RPTPs and cadherins leads to the destabilization of cell-cell adhesions and disruption of protein-protein interactions at the plasma membrane. Meanwhile, unchecked membrane-based RTK signaling sustains the pro-migratory signals initiated by molecules such as PLCγ1.
In this commentary, we discuss the intracellular consequences of RPTP and cadherin cleavage with a focus on the signaling cascades downstream of RTKs that regulate both cell-cell adhesion and migration. We propose that cleavage of RPTPs and cadherins contributes to a migratory phenotype not only through shedding of their adhesive, extracellular domains but also by shifting the subcellular localization of the new intracellular fragments to impact signaling.