Simone Lawson
Constitutive and transient signaling are two distinct processes that play a crucial role in cell signaling and gene expression systems. Constitutive signaling refers to the continuous activation of specific pathways, which may be caused by mutations in certain genes, such as receptor tyrosine kinases (RTKs) or G protein-coupled receptors (GPCRs). These mutations can lead to the receptors existing in a constitutively activated state, potentially acting as oncogenes and contributing to cancer development. On the other hand, transient signaling involves temporary responses to external stimuli. In simple systems, a periodic stimulation elicits an initial transient response, followed by a return to basal activity levels. This adaptation phenomenon is observed when the stimulation has a limited time span or when the stimulated component's timescale is slower compared to downstream processes. Understanding the differences between constitutive and transient signaling is essential for developing targeted therapeutic strategies, especially in the context of cancer and tumorigenesis.
| Characteristics | Values |
|---|---|
| Definition | Transient Signaling: Temporary signaling that initiates the transformation process. |
| Constitutive Signaling: Continuous signaling that maintains the transformed state of malignant cells. | |
| Activation | Transient Signaling: Transient inflammatory signaling activates IL6. |
| Constitutive Signaling: Constitutive inflammatory signaling circuit is formed during the transformation process. | |
| Role in Tumorigenesis | Transient Signaling: A transient inflammatory signal is insufficient to transform normal cells. |
| Constitutive Signaling: Constitutive inflammatory signaling is implicated in tumorigenesis and cancer. | |
| Activation of Pathways | Transient Signaling: Therapeutic strategies should target transient activation pathways differently. |
| Constitutive Signaling: Constitutive activation of pathways may lead to hyperproliferation and cancer. | |
| Examples | Transient Signaling: Transient receptor potential channels are involved in thermoception in cells. |
| Constitutive Signaling: Constitutive inflammatory signaling circuits are found in human cancer cells and ErbB2-driven breast cancer mouse models. |
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What You'll Learn
Therapeutic strategies for constitutive and transient pathways
Therapeutic strategies for targeting constitutive and transient pathways are distinct, as the causes and mechanisms of activation differ between the two.
Constitutive inflammatory signaling pathways are implicated in cancer, with almost all cancers exhibiting abnormal or constitutive inflammatory signaling activation. The feed-forward nature of constitutive inflammatory signaling circuits means that once activated, they maintain their constant activation. For example, in ErbB2-driven breast cancer, a constitutive inflammatory signaling circuit is formed, and deletion of IL6 disrupts this circuit, impairing mammary tumorigenesis. Therapeutic strategies targeting these pathways could focus on disabling specific components of the circuit, such as IL6 in the case of breast cancer.
Constitutive activation of pathways can also be caused by mutated genes, which may act as oncogenes. For example, the HER2 receptor is capable of ligand-independent activation when overexpressed or mutated, leading to constitutive activation and cancer. Therapeutic strategies could thus aim to prevent or compensate for this constitutive activation caused by mutated genes.
Transient inflammatory signaling, on the other hand, initiates the transformation process, but malignant cells then become dependent on the constitutive inflammatory signaling circuit formed during this transformation. Therapeutic strategies targeting transient pathways could focus on preventing or disrupting this initial transformation process. For instance, in the case of neuropathic pain, transient receptor potential vanilloid 1 (TRPV1) plays a pivotal role in nociception by detecting various stimuli. Targeting TRPV1 is a promising strategy for developing novel analgesics, and several pharmacological approaches, including agonists, antagonists, and biological TRPV1 RNA interference, have been explored.
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Constitutive inflammatory signalling in cancer cells
Inflammation is a protective response of the host against infection and tissue damage, which can prevent the spread of pathogens or promote tissue repair. It is estimated that about 25% of cancers are due to chronic infection or other types of chronic inflammation. However, almost all cancers have abnormal or constitutive inflammatory signaling activation.
Constitutive inflammatory signaling in cancer cells may be triggered by extrinsic inflammatory signals from the tumor microenvironment or occur in a cancer cell-intrinsic fashion. For example, activated oncogenes or inactivated tumor suppressors in cancer cells can induce abnormal and constitutive inflammatory signaling.
A recent study established an in vitro co-culture cell transformation system, which discovered that a constitutively activated, feed-forward inflammatory signaling circuit is established during cell transformation. This circuit, comprised of IL6, miR-200c, PTPRZ1, and JNK2, plays a crucial role in cell transformation and tumorigenesis.
In ErbB2 (Neu)-driven breast cancer transgenic mouse models, deletion of IL6 disables this circuit and dramatically impairs mammary tumorigenesis. This demonstrates the importance of constitutive inflammatory signaling in cancer progression and the potential for therapeutic strategies targeting these pathways.
Therapeutic strategies that target constitutively activated pathways should differ from those targeting transient activation. While transient inflammatory signaling can initiate the transformation process, the maintenance of the transformed state of malignant cells is dependent on the constitutive activation of inflammatory signaling circuits formed during transformation.
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Transient inflammatory signalling and cell transformation
Transient inflammatory signals are not enough to transform normal cells. However, transient inflammatory signalling can trigger the transformation of cells that have already accumulated some genetic or epigenetic alterations that provide the basis for oncogenic transformation. In this case, the transient inflammatory signalling from immune cells can initiate the transformation process.
The maintenance of the transformed state of malignant cells is dependent on the constitutively activated inflammatory signalling circuit that is formed during the transformation process. This circuit is comprised of IL6, miR-200c, PTPRZ1 and JNK2 and the transcription factors HSF1, estrogen receptor (ERα), ZEB1, p65/RelA and c-Jun.
In the case of breast cancer, the deletion of IL6 disables this circuit and dramatically impairs mammary tumourigenesis. The constitutive inflammatory signalling circuit is manifest in human cancer cells and ErbB2 (Neu)-driven breast cancer transgenic mouse models.
Constitutive inflammatory signalling in cancer cells may be provoked by extrinsic inflammatory signals from the tumour microenvironment or may occur in a cancer cell-intrinsic fashion. For example, activated oncogenes or inactivated tumour suppressors in cancer cells can induce abnormal and constitutive inflammatory signalling.
Therapeutic strategies that target constitutively activated pathways should be different from those that target transient activation of pathways.
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Constitutive activation of the human S1P5 receptor
Transient and constitutive signalling are two types of cellular signalling mechanisms. Transient signalling is a temporary response to a stimulus, where the system eventually returns to its basal level of activity. On the other hand, constitutive signalling is a persistent form of signalling that continues even after the initial stimulus is removed. This can be due to the mutation of certain genes, resulting in receptors that exist in a permanently activated state.
The human S1P5 receptor is a G protein-coupled receptor (GPCR) that exhibits constitutive activation of specific signalling pathways. S1P5 is a sphingosine-1-phosphate (S1P) receptor, predominantly expressed in the nervous and immune systems. It plays a role in regulating the egress of natural killer cells from lymph nodes and is implicated in immune and neurodegenerative disorders, as well as carcinogenesis.
In a study, S1P5 receptor-expressing HEK293 cells displayed a high level of basal activity for the inhibition of adenylyl cyclase and extracellular signal-regulated kinase (ERK) when cultured in serum containing high levels of S1P. Interestingly, this basal activity was independent of the presence of S1P. The addition of S1P to delipidated serum did not increase the basal S1P5 receptor signalling. Conversely, the constitutive inhibition of forskolin-stimulated adenylyl cyclase was enhanced by S1P in S1P5-HEK293 cells.
Furthermore, the S1P5 receptor has been shown to exhibit ligand-independent inhibition of ERK activity. In CHO cells co-transfected with human S1P5 receptor cDNA and HA-ERK2 cDNA, the inhibition of ERK activity was observed regardless of the presence or absence of S1P in the medium. This suggests that the S1P5 receptor intrinsically inhibits ERK activity through a mechanism that is insensitive to ligand modulation.
The constitutive activation of the S1P5 receptor has important implications for therapeutic interventions. For example, non-selective modulators such as fingolimod and dual S1P1/S1P5 ligands like siponimod and ozanimod have been approved for the treatment of multiple sclerosis, Crohn's disease, and other autoimmune disorders. However, due to the lack of receptor subtype selectivity, these drugs can lead to side effects. Therefore, there is a need to develop highly selective S1P5 ligands to improve the efficacy and reduce the adverse effects of treatments targeting the S1P receptor.
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Constitutive activation of pathways by mutated genes
The constitutive activation of pathways by mutated genes is a critical aspect of understanding cancer development and progression. Constitutive inflammatory signaling is observed in almost all cancers, and it involves the interplay of multiple signaling pathways that are simultaneously activated in cancer cells. This is distinct from transient inflammatory signaling, which initiates the transformation process, but does not maintain the transformed state of malignant cells.
One example of a mutated gene leading to constitutive activation is the mutation of certain Receptor Tyrosine Kinase (RTK) genes. RTKs are transmembrane proteins that perform signal transduction by forming dimers and activating downstream signaling cascades. Mutations in RTK genes can result in receptors that exist in a constitutively activated state. These mutated genes may act as oncogenes, driving tumor progression and metastasis.
Another example is the human S1P5 receptor, a G Protein-Coupled Receptor (GPCR). GPCRs constitute the largest protein family of integral membrane receptors and play a role in regulating specific signaling pathways. The S1P5 receptor-expressing HEK293 cells exhibited high basal activity for both inhibition of adenylyl cyclase and extracellular signal-regulated kinase (ERK) when cultured in serum containing high levels of sphingosine 1-phosphate (S1P). Interestingly, the basal activity was independent of S1P, as constitutive activity remained even in the absence of S1P.
In addition to RTKs and GPCRs, other receptor types can also undergo mutations that lead to constitutive activation. For instance, the HER2 receptor is capable of ligand-independent activation when overexpressed or mutated, resulting in constitutive activation of the pathway and leading to hyperproliferation and cancer.
Furthermore, naturally occurring activating mutations have been associated with various human disease states beyond cancer. For example, mutations in the luteinizing hormone receptor have been linked to male-limited precocious puberty, while mutations in the rhodopsin gene have been implicated in retinitis pigmentosa.
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Frequently asked questions
Constitutive signaling refers to the constant activation of a signaling pathway, which may be caused by the mutation of certain genes. This constant activation can lead to various disease states, including cancer.
Transient signaling refers to the temporary activation of a signaling pathway in response to a stimulus. This initial response is followed by a return to basal or near-basal levels of activity.
Transient inflammatory signaling can initiate the transformation of normal cells into malignant ones, while constitutive inflammatory signaling is necessary to maintain the transformed state of malignant cells.
Therapeutic strategies need to differ between these two signaling processes. A transient inflammatory signal is insufficient to transform normal cells, so targeting transient activation pathways may not be as crucial as targeting constitutively activated pathways in cancer treatment.
