Abstract

The Fer kinase protein, formed by the fusion of the MAN2A1 gene, with the Fer tyrosine kinase gene has been detected in types of cancers such as NSCLC and PDAC. Its ability to promote cancer is influenced by mechanisms, including the Wnt/β signaling pathway an increase in anti-apoptotic proteins and activation of the PI3K/AKT pathway. Additionally Fer plays a role in supporting the growth of melanoma tumors, bladder cancer cells and ovarian cancer cells by phosphorylating insulin receptor substrate four and activating the PI3K/AKT pathway. Furthermore it aids in cell migration and invasion, in adenocarcinoma.

Keywords: Sarcoma Kinase, PI3K/AKT pathway, Wnt/β signaling

Introduction

Fer and Fes are types of proteins known as receptor tyrosine kinases (NRTK) that are part of a group of kinases called Fes and Fer kinases in the NRK category. These proteins have a structure featuring a kinase domain (KD) at one end followed by an SH2 domain and a lengthy N terminal tail containing three coiled-coil domains (Kandel et al.,2019). The N terminal section also includes an FCH motif that along, with the coiled-coil components creates an F BAR domain. This F Bar domain is similar to domains that regulate the actin cytoskeleton and signaling pathways. Members of the Fes/Fer family transmit signals from cell receptors to the interior of the cell. Fer can be found distributed throughout the cell cytoplasm, including within mitochondria indicating its involvement, in pathways (Žagar and Schmidt,2023).

Structural Biology

Feline sarcoma kinase (Fes) and feline sarcoma-related (Fer) kinases belong to the family of receptor tyrosine kinases (NRTK) playing roles, in cell signaling. Their intricate organization boosts their effectiveness, in regulating functions ( Porcellato et al.,2017).

The Fes/Fer kinases possess a Kinase Domain (KD) at the end of their protein structure playing a role, in adding groups to tyrosine residues on specific substrates. This enzymatic function is essential for their involvement, in signaling pathways that control cell growth, development and viability (Wei et al.,2019 ).

The SH2 domain functions, by binding to proteins through recognizing phosphotyrosine residues within amino acid sequences. Fes/Fer kinases can attach to tyrosine phosphorylation sites preparing them for phosphorylation or self-activation. Combining the FCH motif with coiled-coil domains helps form the F BAR domain (Fer/CIP4 homology Bin/Amphiphysin/Rvs) (Zabielska-Koczywas et al.,2017).

The configuration influences how easily membranes move the organization of cell structures. The movement of vesicles. This implies that Fes/Fer play roles, beyond signal transmission (Wei et al.,2019).

Coiled coil regions frequently facilitate the formation of protein dimers or oligomers leading to the development of structures that perform signaling roles. They ensure that interactions associated with Fes/Fer kinases are extended and accurate (Hu et al.,2017).

The connection, between the design and function of Fes/Fer kinases is demonstrated by how they impact cell behavior. The kinase element plays a role in transferring groups to tyrosine residues, which is an essential process in initiating signaling pathways that regulate cell growth, apoptosis, and specialization. Alterations, in this domain could trigger signals commonly observed in cancer cells promoting the proliferation and persistence of cells (Žagar et al.,2023 ).The SH2 domain plays a role, in integrating Fes/Fer kinases into signaling pathways. It helps guide the Fes/Fer kinases to areas, within cells by attaching to phosphorylated tyrosine residues allowing them to carry out their functions (Hu et al.,2019).

The FCH motif and coiled coil domains facilitate the interaction of Fes/Fer kinases with membrane lipids and cytoskeletal components. This allows them to impact, control, and connect biological processes often exploited by cancer cells to aid in invasion and spread ( Kyriazoglou et al.,2022 ).

The N termini of FER and FES are known for their role in facilitating same-type clustering. FES and FER in contrast to other receptor tyrosine kinases (RTKs) may lack corresponding kinase activity and ability to form clusters. Proline insertions disrupting clustering via CC motifs in FES, such as L145P have been shown to enhance kinase activity, oncogenic potential, and independent proliferation of myeloid leukaemia cells. The L145P mutation in FES might interfere with interactions that restrict FES function ( Blay,2011).

Figure 1: Organizational. Blueprint, for triggering FES/FER. Both FES and FER have a layout of domains; F BAR, FX, SH2, PTK domains. FER T is a version of FER found in the testis with a distinct 51 amino acid beginning (Craig,2012) 

Regulation and Activation

Fes and Fer kinases, similar to receptor tyrosine kinases, are tightly regulated to maintain optimal cell function and response to external inputs. The control of these kinases is complex, encompassing processes that may either stimulate or inhibit their activity (de Pins et al.,2021)

Regulation of these kinases involves autoinhibition, where their activity is suppressed until they are signalled to activate. Activation typically occurs via conformational changes induced by interactions with proteins or cellular messengers that remove inhibition and activate the kinase (Chen et al.,2019)

Phosphorylation is a process where one kinase molecule adds a phosphate group to another one. Phosphorylation in Fes/Fer kinases usually takes place in the activation loop of the kinase domain, enhancing its activity (Zhang et al.,2020 ). Protein interactions with signalling molecules are crucial for the function of Fes/Fers. The SH2 domain may interact to phosphotyrosine-containing regions on proteins in activation cascades. To direct Fes/Fer to certain cellular sites where they are involved (Chen et al.,2020)

Effects of Phosphorylation and Signalling Interactions

Phosphorylation controls the activity of Fes/Fer kinases. It acts as a switch to start kinase activity and performs as a mechanism to control the intensity and duration of the signal. For example: Activation: Phosphorylation may cause changes that transform the kinase from an inactive state to an active one. This allows the kinase to add phosphate groups to targets, spreading the signal inside the cell (Zhang et al.,2020). Signal adjustment entails modifying phosphorylation levels to potentially impact the selectivity and function of Fes/Fer by changing their interactions with substances and the effectiveness of their phosphorylation activity (Diaz et al.,2022 ).

Fes/Fer kinases are integrated into signaling networks via their SH2 domains. They might be incorporated into receptor complexes or other signaling structures to phosphorylate and control molecules like as kinases, adaptors, and scaffold proteins(Zhang et al.,2018) . Phosphorylation initiates reaction mechanisms that can either enhance or stop the signal. Negative response strategies may include phosphorylating particular locations on the kinase or introducing phosphatases to remove phosphates from the kinase, thereby reducing its activity ( Nir et al.,2023).

Fes/Fer in Normal Cellular Functions:

Feline sarcoma kinase (Fes) and Feline sarcoma related kinase (Fer) are players, in the structure of cells. Carry out important roles in various regular cell functions.

• In Cell Signaling

The main job of Fes and Fer is to transmit signals within cells relaying information from the surface to the inside. They are involved in pathways that control cell growth, differentiation and movement. For instance Fes is known to be part of signaling pathways related to blood cell formation (hematopoiesis) affecting how blood cells develop and work (Liu et al.,2021).

• Cytoskeletal Arrangement

These enzymes help manage the structure of actin filaments within cells. By adjusting how actin filaments behave they can impact cell shape and mobility. This process is crucial for activities like cell movement, adhesion and maintaining cell structure ( Bae et al.,2022).

• Vesicle Movement

Their FCH domain suggests that these kinases are linked to membrane dynamics and moving vesicles around cells. They likely aid in organizing how vesicles move within a cell, which is important for actions such as taking in substances (endocytosis) or releasing them (exocytosis) (Poganik et al.,2021).

• Cells Response to Stress

Fes/Fer kinases also contribute to how a cell reacts, under stress conditions. When faced with stress or DNA damage these kinases become active. Play a role in the signaling processes that determine how the cell responds to such challenges ( Roskoski ,2019).

Fes/Fer in Oncogenesis

In the realm of cancer development, the disruption of Fes/Fer kinases can play a role, in driving the initiation and advancement of cancer.

• Cell Growth and Viability

Changes in Fes/Fer pathways can result in cell growth and increased cell survival. The overexpression or heightened activation of these kinases has been noted in cancer types. Is often linked to a poor prognosis (Weir,2017).

• Spread to Parts

By influencing regulation Fes/Fer kinases can impact how likely cancer cells are to spread to other parts of the body. They affect cell movement and invasion enabling cancer cells to break from the tumor infiltrate nearby tissues and travel to distant locations (van der Wel et al.,2020).

• Formation of New Blood Vessels

Fes plays a role in angiogenesis the formation of blood vessels for tumor growth. It can influence the pathways that govern cell proliferation and movement which are vital for blood vessel lining cells (Asai et al.,2018).

• Resistance Against Treatment

Cancer cells with increased Fes/Fer activity might show resistance against chemotherapy and radiation therapy. By enhancing pathways that support cell survival these kinases can reduce the effectiveness of treatments that trigger cell death )  Paulin et al.,2018).

• Interplay, with Cancer-Causing Genes and Tumor Suppressing Genes

Fes/Fer kinases can interact with genes that promote cancer growth as genes that suppress tumor formation becoming part of the intricate web of signals controlling cell destiny )  Nir et al.,2023).

Changes, in these kinases or alterations in how they’re expressed can shift the balance, towards causing cancer ( Zhang et al.,2020).

Cancer Pathways Involving Fes/Fer

The Fer kinase was shown to enhance cell proliferation, invasion, and migration. Non-small cell lung cancer (NSCLC) and pancreatic ductal adenocarcinoma (PDAC))  Zhang et al.,2020).. The fusion of the first 13 exons from the MAN2A1 gene with the final 6 exons of the Fer tyrosine kinase gene results in the creation of a recombinant protein known as MAN2A1-FER ) Stanicka  et al.,2018). The fusion protein maintains the tyrosine kinase activity of Fer and has been found in liver tumors, esophageal adenocarcinoma, glioblastoma multiforme, prostate and non-small cell lung malignancies, and ovarian tumors, but not in normal non-tumor tissues. The MAN2A1-FER enhances the growth, ability to spread, and spread to other parts of the body of the cancerous cells that produce it. A fusion transcript is formed by the combination of two different genes ) Debackere et al.,2020).

Fer’s pro-oncogenic activity is associated with several regulatory mechanisms that vary across different forms of cancer. Fer stimulates the Wnt/β-catenin signaling pathway to promote the development and spread of melanoma tumors( Ivanova et al.,2019). The improved survival and proliferation of bladder cancer cells were associated with the upregulation of the anti-apoptotic protein Bcl-2 and the mitogen-activated protein kinase-P38 by Fer (Hu et al.,2019). Fer promotes the uncontrolled growth of ovarian cancer cells by phosphorylating insulin receptor substrate four (IRS4), allowing it to attract the PIK3R2/p85β-subunit of PI3K and activate the PI3K-AKT pathway) Zhang et al.,2018). The metastatic spread of ovarian cancer cells relies on Fer-induced phosphorylation and activation of the hepatocyte growth Factor Receptor (HGFR/MET) in a ligand-independent way. This activates the RAC1-PAK1 signaling pathway, which is essential for the metastatic capability of ovarian cancer cells. Fer enhanced the movement and penetration of malignant cells in pancreatic ductal adenocarcinoma by triggering the STAT3/MMP2 cascade (Fan ,2020).

Conclusions

Fer kinase, a fusion of MAN2A1 and Fer tyrosine kinase genes, is found in cancers like NSCLC and PDAC, promoting growth through Wnt/β-catenin, anti-apoptotic proteins, and PI3K-AKT pathways, and enhancing malignant cell penetration.

Acknowledgment

None .

Conflicts of Interest

None.

References

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